Drug delivery catheters that attach to tissue and methods for their use

ABSTRACT

A drug delivery catheter suited for cardiac procedures. The catheter includes a distal helical coil or other fixation and penetrating element which can be operated from the proximal end of the catheter to engage and penetrate the myocardium. Once delivered to the inside of the heart, the catheter can be used to inject small doses of therapeutic agents to the myocardium. The drug delivery system of the catheter allows for precise control of the dose injected into the heart wall.

This application is a continuation-in-part of co-pending U.S.application Ser. No. 08/816,850 filed Mar. 13, 1997.

FIELD OF THE INVENTIONS

The inventions described below relate to site specific delivery oftherapeutic agents, structures and catheter systems to achieve sitespecific delivery of therapeutic agents, and means for implanting andusing these systems to enable delivery of therapeutic agents to thebody.

These systems also have importance for new procedures that have beencalled percutaneous transmyocardial revascularization or PTMR.

BACKGROUND OF THE INVENTION

It is possible to identify particular sites within the myocardium whichmay benefit from local drug release therapy. Examples of problematictissue which may benefit from local drug release therapy are ischemicsites and arrhythmogenic sites. Different means and methods fordelivering agents to these sites will be disclosed in detail. Thesespecific discussions should in no way limit the scope of the devicesdisclosed for treating other tissues with other agents.

Ischemic Sites

Ischemic tissue is characterized by limited metabolic processes whichcauses poor functionality. The metabolism is limited because the tissuelacks oxygen, nutrients, and means for disposing of wastes. In turn thishinders the normal functioning of the heart cells or myocytes in anischemic region. If an ischemic, or damaged, region of the heart doesnot receive enough nutrients to sustain the myocytes they are said todie, and the tissue is said to become infarcted. Ischemia is reversible,such that cells may return to normal function once they receive theproper nutrients. Infarction is irreversible.

A number of methods have been developed to treat ischemic regions in theheart. Noninvasive systemic delivery of anti-ischemic agents such asnitrates or vasodilators allows the heart to work less by reducingvascular resistance. Some vascular obstructions are treated by thesystemic delivery of pharmacological agents such as TPA, urokinase, orantithrombolytics which can break up the obstruction. Catheter basedtechniques to remove the vascular obstructions such as percutaneoustransluminal coronary angioplasty (PTCA), atherectomy devices, andstents can increase myocardial perfusion. More drastic, but veryreliable procedures such as coronary artery bypass surgery can also beperformed. All of these techniques treat the root cause of poorperfusion.

It should be noted that these therapies are primarily for the treatmentof large vessel disease, and that many patients suffer from poorperfusion within many of the smaller vessels. These smaller vesselscannot be treated with conventional therapies.

The delivery of angiogenic growth factors to the heart via the coronaryarteries by catheter techniques, or by implantable controlled releasematrices, can create new capillary vascular growth within themyocardium. Recent work has shown substantial increases in muscular flowin a variety of in vivo experimental models with growth factors such asbasic fibroblast growth factor (bFGF), vascular endothelial growthfactor (VEGF), and acidic fibroblast growth factor (aFGF). The methodsof delivering these agents to the heart have included implantablecontrolled release matrices such as ethylene vinyl acetate copolymer(EVAC), and sequential bolus delivery into the coronary arteries.Recently similar techniques have been attempted in peripheral vessels inhuman patients with the primary difficulty being systemic effects of theagents delivered. “Angiogenic agents” and “endothelial agents” areactive agents that promote angiogenesis and/or endothelial cell growth,or if applicable, vasculogenesis. This would include factors such asthose discussed that accelerate wound healing such as growth hormone,insulin like growth factor-I (IGF-I), VEGF, VIGF, PDGF, epidermal growthfactor (EGF), CTGF and members of its family, FGF, TGF-a and TGF B. Themost widely recognized angiogenic agents include the following:VEGF-165, VEGF-121, VEGF-145, FGF-2, FGF-I, Transforming Growth Factor(TGF-B), Tumor Necrosis Factor a (TMF a), Tumor Necrosis Factor B (TMFB), Angiogenin, Interleukin-8, Proliferin, Prostaglandins (PGE),Placental Growth factor, Granulocyte Growth Factor, Platelet DerivedEndothilail Cell Growth Factor, Hepatocyte Growth Factor, DEL-1,Angiostatin-1 and Pleiotrophin.

“Angiostatic agents” are active agents that inhibit angiogenesis orvasculogenesis or otherwise inhibit or prevent growth of cancer cells.Examples include antibodies or other antagonists to angiogenic agents asdefined above, such as antibodies to VEGF or Angiotensin 2. Theyadditionally include cytotherapeutic agents such as cytotoxic agents,chemotherapeutic agents, growth inhibitory agents, apoptotic agents, andother agents to treat cancer, such as anti-HER-2, anti CD20, and otherbioactive and organic chemical agents.

Polypeptide agents may be introduced by expression in vivo, which isoften referred to as gene therapy. There are two major approaches forgetting the nucleic acid (optionally containing a vector) into thepatients cells: in vivo and ex vivo. For in vivo delivery, the nucleicacid is injected directly into the patient, usually at the site wheredesired. For ex-vivo delivery, the patients cells are removed, thenucleic acid is introduced into these isolated cells, and the modifiedcells are administered to the patient either directly or viaencapsulation within porous membranes that are implanted into thepatient (see U.S. Pat. Nos. 4,892,538 and 5,283,187).

The preferred embodiment of this invention is the delivery oftherapeutic molecules from micro drug delivery systems such asliposomes, nanoparticles, biodegradable controlled release polymermatrices, and biodegradable microspheres which are well known in theliterature. These have been described briefly in U.S. application Ser.No. 08/816,850.

The agents to be delivered may include one or more small molecules,macromolecules, liposomal encapsulations of molecules, microdrugdelivery system encapsulation of therapeutic molecules, covalent linkingof carbohydrates and other molecules to a therapeutic molecules, andgene therapy preparations. These will be briefly defined.

“Small molecules” may be any smaller therapeutic molecule, known orunknown. Examples of known small molecules relative to cardiac deliveryinclude the antiarrhythmic agents that affect cardiac excitation. Drugsthat predominantly affect slow pathway conduction include digitalis,calcium channel blockers, and beta blockers. Drugs that predominantlyprolong refractoriness, or time before a heart cell can be activated,produce conduction block in either the fast pathway or in accessory AVconnections including the class IA antiarrhythmic agents (quinidine,procainimide, and disopyrimide) or class IC drugs (flecainide andpropefenone). The class III antiarrhythmic agents (sotolol oramiodorone) prolong refractoriness and delay or block conduction overfast or slow pathways as well as in accessory AV connections. Temporaryblockade of slow pathway conduction usually can be achieved byintravenous administration of adenosine or verapamil. [Scheinman,Melvin: Supraventricular Tachycardia: Drug Therapy Versus CatheterAblation, Clinical Cardiology Vol 17, Suppl. II-11-II-15 (1994)]. Manyother small molecule agents are possible, such as poisonous or toxicagents designed to damage tissue that have substantial benefits whenused locally such as on a tumor. One example of such a small molecule totreat tumors is doxarubicin.

A “macromolecule” is any large molecule and includes proteins, nucleicacids, and carbohydrates. Examples of such macromolecules include thegrowth factors, Vascular Endothelial Growth Factor, basic FibroblasticGrowth Factor, and acidic Fibroblastic Growth Factor, although othersare possible. Examples of macromolecular agents of interest for localdelivery to tumors include angiostatin, endostatin, and otherantiangiogenic agents.

A “Liposome” refers to an approximately spherically shaped bilayerstructure comprised of a natural or synthetic phospholipid membrane ormembranes, and sometimes other membrane components such as cholesteroland protein, which can act as a physical reservoir for drugs. Thesedrugs may be sequestered in the liposome membrane or may be encapsulatedin the aqueous interior of the vesicle. Liposomes are characterizedaccording to size and number of membrane bilayers.

A “gene therapy preparation” is broadly defined as including geneticmaterials, endogenous cells previously modified to express certainproteins, exogenous cells capable of expressing certain proteins, orexogenous cells encapsulated in a semi-permeable micro device. Thisterminology is stretched beyond its traditional usage to includeencapsulated cellular materials as many of the same issues ofinterstitial delivery of macrostructures apply.

The term “genetic material” generally refers to DNA which codes for aprotein, but also encompasses RNA when used with an RNA virus or othervector based upon RNA. Transformation is the process by which cells haveincorporated an exogenous gene by direct infection, transfection, orother means of uptake. The term “vector” is well understood and issynonymous with “cloning vehicle”. A vector is nonchromosomal doublestranded DNA comprising an intact replicon such that the vector isreplicated when placed within a unicellular organism, for example by aprocess of transformation. Viral vectors include retroviruses,adenoviruses, herpesvirus, papovirus, or otherwise modified naturallyoccurring viruses. Vector also means a formulation of DNA with achemical or substance which allows uptake by cells. In addition,materials could be delivered to inhibit the expression of a gene.Approaches include: antisense agents such as synthetic oligonucleotideswhich are complimentary to RNA or the use of plasmids expressing thereverse compliment of a gene, catalytic RNA's or ribozymes which canspecifically degrade RNA sequences, by preparing mutant transcriptslacking a domain for activation, or over express recombinant proteinswhich antagonize the expression or function of other activities.Advances in biochemistry and molecular biology in recent years have ledto the construction of recombinant vectors in which, for example,retroviruses and plasmids are made to contain exogenous RNA or DNArespectively. In particular instances the recombinant vector can includeheterologous RNA or DNA by which is meant RNA or DNA which codes for apolypeptide not produced by the organism susceptible to transformationby the recombinant vector. The production of recombinant RNA and DNAvectors is well understood and need not be described in detail. Suchgene therapy preparations could be delivered in a variety of fluidagents, one of which is phosphate buffered saline.

Details on microencapsulated cells are described in U.S. Pat. No.5,698,531 and additional details on the delivery of genetic material aredescribed in U.S. Pat. No. 5,704,910. Both of these patents describe thepotential of delivering such agents endoluminally within a blood vessel.Neither of these provides a means to deliver such agents at a depthwithin the heart muscle, and neither of them recognizes the potential ofthis approach. U.S. Pat. No. 5,661,133 does recognize the potential fordelivering genes to the heart, but does not describe the means ofdelivery other than by injection.

U.S. Pat. No. 5,244,460 issued to Unger describes a method ofintroducing growth factors over time by delivering them through fluidcatheters into the coronary arteries, but this does not result inefficient delivery of these agents to the ischemic tissue. If these orother agents are delivered to the coronary, a region of tissue that isequivalent to that supplied by the artery will receive the therapeuticagents. This may be substantially more tissue than is in need of localdrug delivery therapy. Further, if a vessel is occluded, the growthfactors will act in the tissue which the coronary arteries successfullyperfuse. As the underlying problem of ischemic tissue is poor perfusion,excess growth factor must be delivered in order to obtain the desiredeffects in the poorly perfused tissue. Further, growth factors may causeunwanted angiogenesis in tissues where inappropriately delivered. Thecornea is described by Unger as such a location, but perhaps morecritical is inappropriate delivery of these factors to the brain.Further, placement of delivery devices within these coronary arteries asUnger describes will tend to obstruct these arteries and may augmentocclusive thrombosis formation. There is a significant need for a meansand method of minimizing the amount of growth factors for introducingangiogenesis by delivering these agents only to the site where they aremost needed.

In addition to a device for delivering growth factors, there arecomplications with clinically acceptable procedures where specialdevices for delivering agents to ischemic tissue will be useful. Afteropening vessels using PTCA, the vessels often lose patency over time.This loss of patency due to restenosis may be reduced by appropriatepharmacological therapy in the region of the artery. There is a need fornew techniques that will enable pharmacological therapy to reduce theincidence of restenosis.

Arrhythmogenic Sites

Cardiac arrhythmias are abnormal rhythmic contractions of the myocardialmuscle, often introduced by electrical abnormalities, or irregularitiesin the heart tissue, and not necessarily from ischemic tissue.

In a cardiac ablation procedure, the arrhythmogenic region is isolatedor the inappropriate pathway is disrupted by destroying the cells in theregions of interest. Using catheter techniques to gain venous andarterial access to the chambers of the heart, and possibly trans septaltechniques, necrotic regions can be generated by destroying the tissuelocally. These necrotic regions effectively introduce electricalbarriers to problematic conduction pathways.

U.S. Pat. No. 5,385,148 issued to Lesh describes a cardiac imaging andablation catheter in which a helical needle may be used to deliver fluidablative agents, such as ethanol, at a depth within the tissue toachieve ablation. Lesh further describes a method of delivering apharmacological agent to the tissue just before performing the chemicalablation procedure to temporarily alter the conduction of the tissueprior to performing the ablation. Such temporary alteration of tissuehas the advantage of allowing the physician to evaluate the results ofdestructive ablation in that region prior to actually performing theablation. This method of ablation has the advantage that the ablativefluid agents are delivered to essentially the same tissue as thetemporary modifying agents. However, with ablative fluid agents it isdifficult to control the amount of tissue which is destroyed—especiallyin a beating heart, and ablative RF energy is in common use because ofits reproducible lesions and ease of control. There is a need for anablation catheter that provides for both temporary modification oftissue conductivity by delivery of therapeutic agents at a depth withinthe tissue and delivery of RF energy from the same structure within theheart wall that was used to deliver the therapeutic agents.

U.S. Pat. No. 5,527,344 issued to Arzbaecher describes a pharmacologicalatrial defibrillator and method for automatically delivering adefibrillating drug into the bloodstream of a patient upon detection ofthe onset of atrial arrhythmias in order to terminate the atrialarrhythmias, and is herein incorporated by reference. By deliveringagents to a blood vessel, Arzbaecher requires systemic effects to beachieved in order to terminate the atrial arrhythmias. The advantages oflocal drug delivery are completely absent from the system described.There is a need for a system and method to transiently treat atrialarrhythmias by local delivery of pharmacological agents which willeffect the excitation of the cardiac tissue locally.

There have been many patents describing systems for delivering antiinflammatory agents to the endocardial surface of the heart. Suchsurface delivery is less viable for regions at a depth within thetissue. Further, because of the volume of fluid moving by the innersurfaces of the heart, higher concentrations may be required at thesurface to counteract the effects of dilution. These higher doses resultin greater likelihood of problematic systemic effects from thetherapeutic agents. Delivering agents within the tissue will minimizethe dilution of agents, and decrease the possibility of the agents beingdelivered to inappropriate sites. This is particularly important withgrowth factors whose systemic affects are not well documented, just asit is important for antiarrhythmic agents whose pro-arrhythmia systemiceffects have been recognized. There is a need for a means to deliveragents to ischemic and arrhythmogenic sites within the myocardium.

The prior art of devices to deliver substances at a depth within theheart is not extensive. U.S. Pat. Nos. 5,447,533 and 5,531,780 issued toVachon describe pacing leads having a stylet introduced antiinflammatory drug delivery dart and needle which is advanceable from thedistal tip of the electrode. U.S. Pat. No. 5,002,067 issued toBerthelson describes a helical fixation device with a groove to providea path to introduce anti-inflammatory drug to a depth within the tissue.U.S. Pat. No. 5,324,325 issued to Moaddeb describes a myocardial steroidreleasing lead whose tip of the rigid helix has an axial bore which isfilled with a therapeutic medication such as a steroid or steroid baseddrug. None of these patents provide a means for site specific deliveryof agents as all applications of the drug delivery systems are at thelocation selected for pacing. None of these has provided a means ormethod for delivering agents to ischemic or infarcted tissues. Of these,only Vachon and Moaddeb provide a means for effectively delivering theanti-inflammatory agents to a depth within the myocardium. U.S. Pat. No.5,551,427 issued to Altman describes a catheter system capable ofdelivering drugs to the heart at a depth within the heart tissue.

U.S. Pat. No. 5,431,649 issued to Mulier describes a hollow helicaldelivery needle to infuse the heart tissue with a conductive fluid priorto ablation to control the lesion size produced. The system does nothave drug delivery capabilities.

None of the prior art provides controlled release matrix delivery down aneedle or helix to a depth within the heart tissue. None of the priorart provides for a distally located osmotic pump to deliver agents to adepth within the heart tissue. None of the prior art provides a means ofdelivering agents transiently to a depth within the heart tissue upondemand. None of the prior art provides a means to clear the cathetersystem of one drug and effectively replace it with a second drug. Noneof the prior art provides a low impedance conductor to the drug deliverystructure for performing ablation after the delivery of a drug. None ofthe prior art includes the use of macromolecular controlled releasematrices such as ethylene vinyl acetate co-polymer to deliver agentswith large molecular weights to a depth within the heart tissue.

Local drug delivery provides many advantages. Approaches for localdelivery of agents at a depth within a tissue enables the delivery ofdrugs to sites where they are most needed, reduces the amount of drugsrequired, increases the therapeutic index of the particular dosingregime, and increases the control over the time course of agentdelivery. These, in turn, improve the viability of the drugs, lower theamount (and cost) of agents, reduce systemic effects, reduce the chanceof drug-drug interactions, lower the risk to patients, and allow thephysician to more precisely control the effects induced. Such localdelivery may mimic endogenous modes of release, and address the issuesof agent toxicity and short half lives. Approaches for local drugdelivery using a catheter based system with a distally located tissuepenetrating element have applications in organs such as the heart,pancreas, esophagus, stomach, colon, large intestine, or other tissuestructure to be accessed via a controllable catheter.

Local drug delivery to the heart is known. In U.S. Pat. No. 5,551,427,issued to Altman, implantable local drug delivery at a depth within theheart is described. The patent shows an implantable helically coiledinjection needle which can be screwed into the heart wall and connectedto an implanted drug reservoir outside the heart. This system allowsinjection of drugs directly into the wall of the heart acutely byinjection from the proximal end, or on an ongoing basis by a proximallylocated implantable subcutaneous port reservoir, or pumping mechanism.The patent also describes implantable structures coated with coatingwhich releases bioactive agents into the myocardium. This drug deliverymay be performed by a number of techniques, among them infusion througha fluid pathway, and delivery from controlled release matrices at adepth within the heart. Controlled release matrices are drug polymercomposites in which a pharmacological agent is dispersed throughout apharmacologically inert polymer substrate. Sustained drug release takesplace via particle dissolution and slowed diffusion through the pores ofthe base polymer. Pending application Ser. No. 08/816,850 by Altman andAltman, and Ser. No. 09/131,968 by Altman and Ser. No. 09/177,765 byAltman describe and Ser. No. 09/257,887 by Altman and Altman describesome additional techniques for delivering pharmacological agents locallyto the heart. The techniques described herein are all incorporated byreference.

Recently, local delivery to the heart has been reported of therapeuticmacromolecular biological agents by Lazarous [94 Circulation, 1074-1082(1996)], plasmids by Lin [82 Circulation 2217-2221 (1990)], and viralvectors by French [90 Circulation 2414-2424 (November 1994)] andMuhlhauser [3 Gene Therapy 145-153 (1996)]. March [89 Circulation1929-1933 (May 1994)] describes the potential for microsphere deliveryto the vessels of the heart, such as to limit restenosis.

U.S. Pat. No. 4,296,100 issued to Franco describes direct injection ofFGF into the heart but specifically does not call out cathetertechniques. U.S. Pat. No. 5,693,622 issued to Wolff describes promotersfor gene therapy to the heart, but does not enable the delivery of DNAsequences through either vascular or cardiac catheter, or by theinjection into the interstitial spaces of the heart.

U.S. Pat. Nos. 5,807,395; 5,431,649 and 5,405,376 issued to Mulier andU.S. Pat. No. 5,385,148 issued to Lesh describe helical needles for useduring an ablation procedure, and are limited to ablation catheter uses.They also require the presence of high conductors capable of carryingenergy to perform ablation, and do not provide for instruction on how toaccess different regions of the myocardium and confirm the placement ofa device prior to the delivery of fluid agent, nor do they describe ameans for guaranteeing that a precise dose is delivered of a particularfluid agent. U.S. Pat. 5,840,059 issued to March describes a means ofdelivering therapeutic agents into a channel within the heart, butsuffers the serious limitation in that the material will likely not beretained in the channels. The viscous carrier suggested by March to helpretain the material within the channels poses substantial risk asembolic material should it escape from the channels and be released intothe endocardial chamber.

SUMMARY

The devices and methods described below provide for the delivery ofsmall doses of therapeutic agents within the body, in particular theheart. The catheters described below include a distal helical coil orother fixation and penetrating element which can be operated from theproximal end of the catheter to engage and penetrate the myocardium.Once delivered to the inside of the heart, the catheter can be used toinject small doses of therapeutic agents to the myocardium. The drugdelivery system of the catheter allows for precise control of the doseinjected into the heart wall.

The devices may be used to administer a number of therapeutic agentsfollowed by additional therapeutic agents or passive agents intended toensure that the intended dose is delivered notwithstanding the deadspace of the catheter. Therapeutic agent in the catheter dead space isflushed from the dead space into the heart. Calibrated therapeutic agentreservoirs account for the dead space, and passive agent reservoirsprovide a ready source for flushing fluid. The reservoirs may be filledprior to a catheterization, and inserted into a catheter proximal handleso that they are easily operated during the catheterization. Thereservoirs are connected to the drug delivery lumen of the infusioncatheter through a valve which may be selectively operated to align oneor the other reservoir to the drug delivery lumen of the catheter.Additionally, the drug reservoirs may be connected to the valve throughflexible distensible lengths of tubing, permitting easy manipulation ofthe reservoirs for filling and placement in the proximal handle.

The catheter described herein can be used for a number of procedures,including local delivery of angiogenic agents, controlling heart rateduring heart procedures and transmyocardial revascularization.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a shows a partial cross sectional view of a drug deliverycatheter.

FIG. 1b shows a cross sectional view of the proximal portion of a duallumen drug delivery catheter.

FIG. 1c shows a partial cross sectional view of a distal portion of drugdelivery catheter with a hollow fixation helix.

FIG. 2 shows a partial cross sectional view of a distal portion of adrug delivery catheter with a short needle located in the axis of thehelical fixation device.

FIG. 3a shows a partial cross sectional view of the distal portion of adrug delivery catheter which incorporates an osmotic pump.

FIG. 3b shows a partial cross sectional view of the distal portion of adrug delivery catheter which incorporates an osmotic pump.

FIG. 4 shows a partial sectional view of a distal portion of a drugdelivery catheter.

FIG. 5a shows a partially sectional view of the distal portion of a drugdelivery catheter with a rate control barrier.

FIG. 5b shows a partially sectioned view of the distal portion of a drugdelivery catheter with a second lumen for stylet use duringimplantation.

FIG. 5c is a cross sectional view of bi-lumen catheter of FIG. 5b.

FIG. 6 shows a partially sectional view of a subcutaneous injectionport, and a drug delivery catheter.

FIG. 7 shows a partially sectional view of the distal end of a drugdelivery catheter.

FIG. 8 shows a partially sectional view of a filled helical drugdelivery fixation means.

FIG. 9 shows a partially sectioned view of the distal end of a drugdelivery catheter.

FIG. 10a shows a partially sectioned view of a drug delivery catheterwith a nitinol transient delivery means.

FIG. 10b shows a partial cross sectional view of a distal portion ofdrug delivery catheter with a vapor pressure transient delivery means.

FIG. 11 shows a sectional view of a drug delivery catheter placedthrough a guide catheter into the left ventricle of a human heart.

FIG. 12 shows an infusion catheter.

FIG. 13 shows a handle of an infusion catheter.

FIG. 14 shows a handle of a steerable guide catheter.

FIG. 15a through FIG. 15f shows a distal end of a steerable guidecatheter with a coaxial infusion catheter system.

FIG. 16 shows a steerable guide catheter with a slotted torque tubebending element.

FIGS. 16a, 16 b and 16 c re cross sections of the steerable guidecatheter of FIG. 16.

FIG. 17 shows a distal end of a steerable guide catheter with centrallylocated infusion catheter.

FIG. 18 shows a schematic of a preferred technique for performingpercutaneous transmyocardial revascularization and therapeutic deliverywith a helical needle catheter system.

FIG. 19 shows one embodiment of the distal end of an infusion and guidecatheter pair.

FIG. 20 shows the distal end of a catheter with pincher fixation means.

FIG. 20a is a cross section of the catheter illustrated in FIG. 20.

FIG. 21 shows a distal end of a helical needle infusion catheter.

FIG. 22a through FIG. 22c show preformed shapes of guide catheters foraccessing different regions in the left ventricle of a heart.

FIG. 23 shows a handpiece for a catheter system.

DETAILED DESCRIPTION OF THE INVENTION

New concepts for delivering agents for the treatment of heart failure,ischemia, arrhythmias, and restenosis are disclosed. The main embodimentconsists of transvenous or transarterial catheter delivery techniquesfor delivering agents directly to a chosen site within the heart at adepth within the heart tissue. Hollow helical delivery devices, needledelivery devices, and implantable controlled release matrices may beinserted such that metabolic agents, anti ischemic agents, growthfactors, antiarrhythmic agents, anti-inflammatory agents, gene therapypreparations, and combinations of these agents may be delivered directlyto the tissue that can benefit most from these agents. These systemshave applicability in many areas of the body, particularly those whichmay be accessed via a body duct or vessel.

These drug delivery structures may be made from drastically differentmaterials depending upon whether the device is to be used chronically oracutely. For example, metal components in the implantable embodimentswhich are formed of a Platinum Iridium alloy consisting of ninetypercent Platinum and ten percent Iridium will typically be replaced with316L surgical stainless steels in the acute embodiments. Likewiseimplantable grades of silicone and polyurethane will be replaced withpolyurethanes, polyolefins, fluoropolymers, nylon, and the like in theacute uses of the devices. As a means of addressing this, the termcatheter is used to describe both chronically and acutely implantablesystems.

FIG. 1a shows a first cardiac drug delivery catheter with a sectionalview of the proximal end. Pin 2 is shown mechanically crimped at crimp 6to electrically conductive helical coil 8. Crimp 6 is typically coveredby compliant polymer molding 4 which may form a seal with a catheterport on a drug delivery reservoir or pumping means (not shown). Furthermolding 4 and catheter body 14 may have external sealing rings toprovide fluid tight seals with such ports. Pin 2 connects to internaltubing 10 with lumen 12 which travels the entire length of the catheterto the distal end 22 and allows for fluid agents to be delivered througha fluid pathway in the fixation end 24. The catheter body 14, 20, and 22covers the coil 8 along the entire length of the delivery system distalto crimp 4 such that rotation of pin 2 or crimp 4 relative to proximalcatheter body 14 will result in rotation of coil 8 within catheter body14, 20, and 22 and deploy fixation mechanisms at fixation end 24. Thecentral lumen 12 in some embodiments may also be used to pass a styletfor use during implantation to facilitate the implantation procedure.

The catheter shown in FIG. 1a differs from those in the prior art inthat it is made of permanently implantable materials, it has electricalcontinuity from end to end for sensing cardiac activity, it has a lumenfor conveying fluidic agents along its length, and a hollow fixationmeans for delivering fluidic agents to a depth within the heart tissue.The materials selected must be able to be implanted for a period on theorder of a week without rejection by the patient in order to delivergrowth factors over an extended period of time to the patient, or forpermanent implantation to provide for transient drug delivery driven bya proximal reservoir and energy source. The catheter body 14, 20, and 22would be an implant grade polyurethane or silicone, and the distalfixation mechanism at fixation end 24 would be a platinum iridium alloy.The catheter has a single electrode to facilitate implantation bysensing the electrical potential at the implant site. None of the priorart contains this combination which is necessary to achieve theadvantages of ease of implantation, and delivery of fluidic agents to adepth within the heart from a proximally located reservoir.

FIG. 1b shows another embodiment of the proximal end of a catheterdelivery system in which a second stylet lumen 66 is provided forinsertion of a stylet. Such an additional lumen may be useful to preventcontamination of the inner drug delivery tubing 62 during implantation.Inner tubing 62 is connected to pin 52 at connection 56, which may beperformed simply by pulling tubing 62 over pin 52 at connection 56.Electrically conductive coil 60 surrounds tubing 62 and may be rotatedrelative to outer jacket or catheter body 58 of the delivery system.After implantation using a stylet in stylet lumen 66, pharmacologicalagents may be delivered to the heart by a fluid pathway defined bydelivery system lumen 64. The different tubing barriers are shown moreclearly in tubing cross section 68. In this specific embodiment, crimp54 which connects pin 52 and coil 60 is not overmolded, and a single setof seals 70 are shown molded over the proximal end of catheter body 58.Seals 70 prevent migration of fluids into the catheter after connectionwith a catheter port in a drug delivery reservoir or pumping means. Inone embodiment, the distal end of the drug delivery catheter shown inFIG. 1b would be the distal embodiment shown in FIG. 5b. The use of sucha second lumen with a drug delivery system for delivery of agents to adepth within the heart does not appear in the prior art.

FIG. 1c shows a partial cross sectional view of a distal portion of adelivery catheter which is to be implanted endocardially by theappropriate venous or arterial access. Here, a simple pathway for fluidto pass from a subcutaneous reservoir or delivery pump (not shown)through a deployable helical needle is provided. Helical coil 102 isshown here as being multifilar, but could be single filar as well.Varying the number of filars allows the flexibility of the catheter aswell as the coils ability to transmit torque to the helical fixationstructure 114 which is formed of a radio opaque material such as Pt/Ir90/10. The helical fixation structure is screwed into the heart byturning the coil 102 inside the outer catheter body 106. A fixedstructure 130, on the inner wall of the catheter body 106, foradvancement and retraction of the helical fixation structure 114, forcesthe helical fixation structure 114 to advance from the distal end of thecatheter when the central helical coil 102 and tube for drug delivery104 are rotated counterclockwise. Fixed structure 130 is typicallyformed from a radio opaque material to assist the implanting physicianin identifying when helical fixation structure 114 has been deployed.Fixed structure 130 also will retract the helical fixation structure 114from the heart wall when the coil 102 is rotated clockwise. Thesedirections could easily be reversed by varying the direction of thewinding of the helical fixation structure 114. The helical coil 102which provides torque to implant the helical fixation structure 114 iswelded or crimped to the torque delivery structure 110 at the coil totorque delivery structure connection 128. Here, the coil cross section108 is shown crimped at connection 128. Proximal stop 124, and distalstop 112 are raised portions on the inside of the catheter body 106, andprevent the helical fixation structure 114 from being too far extendedor retracted. A fluid path is provided from the proximal end of thecatheter (not shown) by tube for drug delivery 104 which connects to thetube fitting 126 of the hollow helical fixation structure 114. Thehollow helical fixation structure 114 may have a number of small holesor helix apertures 116, 118, 120, 122 along its length where it ispenetrated into the heart tissue. These holes provide a means fordelivering agents into the heart tissue at a depth within the tissue.Helix tip 132 is sharp to facilitate penetration of the heart tissue,and acts as a further opening for the agents to migrate from the tissue.In some embodiments the helix apertures may be on only the distalportion of the helix to minimize the possibility of agents beingdelivered within the heart chambers. In other embodiments, the helixapertures are not present to maximize the structural integrity of thefixation helix. Where this is the case, all agents would be delivered tothe heart from the aperture at the hollow helix tip 132. The fixationhelix 114 is rigidly attached to the torque delivery structure 110 toprovide means for advancement when coil 102 is rotated.

FIG. 1c shows a means for delivering agents by a fluid path to a depthwithin the heart tissue, and is novel in that it delivers a wide varietyof agents by way of a fluid pathway to a depth within the tissue from aproximally located reservoir and is able to transmit electrical energyalong helical coil 102 to and from helical fixation structure 114 by wayof electrically conductive torque delivery structure 110. It can beviewed as the distal end of the implantable catheter whose proximal endis described in FIG. 10a or FIG. 10b. In one embodiment, the device ofFIG. 1 could be used for chronic delivery of antiarrhythmic agents toalter local conduction either continuously, or dynamically on demandbased upon the signals sensed through helical fixation means structure114. Such algorithms have been described for pharmacological atrialdefibrillation by Arzbaecher in U.S. Pat. No. 5,527,344. In otherembodiments agents for a variety of disease states may be continuouslyinfused by the fluid pathway presented such that they are delivered to aspecific site within the myocardium. The proximal end of the cathetermay be connected to a drug pumping mechanism or to a proximally locatedreservoir. Such proximal devices may be implantable or exist outside thepatient. Access to implantable proximal devices for refilling agents iseasily achieved with a subcutaneous port.

Transient delivery of pharmacological agents based upon demand requiresthe presence of electrical conductors along the length of the drugdelivery catheter to monitor the electrical action of the heart.Delivering of agents upon demand will alter the local conduction orautomaticity of the cardiac tissue and allow for the arrhythmia to betreated. A very small amount of drug will be required to treat aspecific location within the tissue, which has substantial benefits. Asmall doses of antiarrhythmic agents will minimize the need to refillthe proximally located reservoir; and reduce the systemic effects thatresult from large drug doses as well as the effects that the agents willhave on normally functioning cardiac tissue. In one application of thisembodiment, the device would be implanted in the right atrium at alocation determined to be most likely to terminate a patientssupraventricular arrhythmia. A subcutaneous infusion pump could betriggered by the electrical activity of the heart, and a very smallregion of tissue would receive local drug delivery for a preprogrammedduration. A small region of heart would then be modified such thatcardiac excitation wavefronts would be altered by the tissue treated.This will provide substantial advantages to patients, even if not 100percent effective. Typical drugs delivered would be antiarrhythmicagents such as those described by in U.S. Pat. No. 5,551,427 issued toAltman.

In a separate embodiment, the device described in FIG. 1c could be anacute catheter made of non-implantable materials. Catheter body 106would be formed of polyurethane or a fluoropolymer such as ETFE or PTFE;helical fixation structure 114, and torque delivery structure 110 wouldlikely be made of Titanium or 316L stainless steel. Such a catheterwould be used for acute ablation procedures in which antiarrhythmicagents are delivered to temporarily alter the conduction of the heart atthe site of the implanted helix. Electrical mapping and stimulationmeasurements may then be made to determine if the region is appropriateto be ablated. If the region is not appropriate the device may beremoved and repositioned. If the region affected by the anti arrhythmicagents which effect tissue conduction is desired to be ablated, RFenergy may be delivered from the electrically active helix to a largesurface electrode, such as that used in electrocautery. The first regionablated will be that equivalent to the surface of the implanted helix.The helical coil 102 is highly conductive to enable RF energy to beconducted to the distal fixation structure to allow ablation of theregion immediately at the fixation structure. Such a high conductivitycoil could be formed from a number of wires wrapped in parallel in whicheach wire has a high conductivity silver core jacketed by an MP35N noncorrosive alloy. This catheter provides for both temporary modificationof tissue conductivity by delivery of therapeutic agents to a depthwithin the tissue, and delivery of RF energy from the structure withinthe heart wall that was used to deliver the therapeutic agents. Theablation catheters described in the prior art do not simultaneouslyprovide for drug delivery and ablation from the same structure.

FIG. 2 shows another distal portion of a delivery catheter forendocardial placement. The operation is similar to that shown in FIG. 1,and is applicable to all embodiments described. However, here the solidfixation structure 202 does not provide a fluid path for delivery ofagents. The fluid pathway is instead provided by a centrally locatedhollow needle 204. Apertures could also be made along the needle toprovide more exposure to the tissue within the heart wall. Fluid agentsmay flow down the inside of a connecting tube 104, inside the hollowneedle 204, and out through apertures in the surface (not shown) and theneedle tip 206. Agents are delivered via the needle to a depth withinthe tissue. The solid fixation structure advances in the same manner asdescribed in FIG. 1, and may be rigidly attached to the torque deliverystructure 110 by a weld 208. Other methods of connection are alsopossible. The primary advantage of this design is that the solid helicalfixation structure 202 is structurally more robust than that of thehollow structure shown in FIG. 1c. This will facilitate implantation ofthe structure.

Other embodiments which incorporate osmotic pumps, controlled releasematrices, membrane barriers, and catheter based transient delivery meansincrease the ability to control the delivery of agents to a depth withinthe heart tissue. They have substantial advantages in delivering agentssuch as growth factors and gene therapy preparations in that very smallamounts of the agents are required, the delivery is controlled overtime, and the agents are delivered to a depth within the heat.

FIG. 3 shows an osmotic pump located at distal end of a catheter todrive therapeutic agent into heart tissue using a needle 318 or hollowhelix (not shown) fluid transport system as described. Agents may bedelivered via the fluid pathway previously described, through the checkvalve 302, and into the drug volume or drug reservoir 304. After thedrug volume 304 is full, agents will migrate out the needle tip 320, andapertures 322. In this way, the drug volume 304 may be loaded before,during, or after implantation from the proximal end of the drug deliverycatheter. Once advanced into the heart tissue, diffusion of water acrossthe semipermeable membrane 312 will occur because of the presence of theosmotic salt 310. As this salt expands with hydration, pressure will beexerted against the flexible barrier 306 and the rigid osmotic pumphousing 308. The expansion of the osmotic salt 310 is tantamount to aconstriction of the drug volume 304 and as the check valve 302 is closedto reverse flow, the agents are forced through the delivery structureand into the heart wall. Here, the pathway to the needle tip 320 is byway of proximal needle apertures 316 and proximal needle opening 324within the drug volume 304. The rigid support 314 provides means ofsupporting the helical fixation means and the needle delivery structure.

Placing an osmotic pump directly at the site where agents are deliveredhas the benefit of limiting the amount of agent in the system. Indevices where the agent in the filling tube can be removed, thesite-specific osmotic pump does not require a long length of tubingfilled with pharmacological agent. This may be particularly useful foragents whose systemic effects are undesirable or unknown. To deliveragents by a fluid pathway along the length of a catheter system willrequire a length of tubing to be filled with the appropriate agent.Although minimizing the cross sectional area of such a tube will resultin a reduction of the problem of excessive agents, putting the pump atthe site for delivery completely eliminates the problem. Placing theosmotic device at the end of the catheter tube provides the advantageousmeans for follow-up delivery after the pump has delivered all of theagents in the drug volume 304. Further, a very small amount of agent maybe all that is required and the osmotic pump may be small enough to beplaced on a catheter at the site for delivery. Although catheter basedosmotic pumps have been described for steroid elution to the surface ofthe endocardium, there is no prior art for such catheter based osmoticpumps capable of delivering pharmacological agents at a depth within atissue with the means disclosed here. Further, there have been nodescriptions of catheter based osmotic pumps which may be filledproximally after implant and whose agents may be altered duringdelivery. Such delivery techniques have substantial advantages formacromolecules such as growth factors and genetic material. Further,they may allow for very controlled delivery of microsphere or micelleencapsulated agents such as may be required for gene therapy.

The drug reservoir can be either a solution or a solid formulationcontained in a semipermeable housing with controlled water permeability.The drug is activated to release in solution form at a constant ratethrough a special delivery orifice. The release of drug molecules orencapsulated drug molecules from this type of controlled release drugdelivery system is activated by osmotic pressure and controlled at arate determined by the water permeability and the effective surface areaof the semipermeable housing as well as the osmotic pressure gradient.Devices which use hydrodynamic pressure gradients are similar except thesemipermeable membrane is replaced by an opening, and the osmotic saltis replaced by an absorbent and swellable hydrophilic laminate.

FIG. 3b shows a partially sectional view of another embodiment of thedistally located osmotic pump. Here check valve 402 is located at theproximal end of the needle structure 404 which is continuous through thedrug volume 304. This needle structure 404 provides more structuralstability to the drug delivery device and guarantees that there will bea fluid pathway even after the osmotic action has driven all of theagent out of the drug volume 304. Further, a section of seal 406 isshown attached to the inside of the catheter body. Osmotic pump housing308 moves within seal 406 which acts to prevent migration of fluids intothe catheter body.

FIG. 4 shows another embodiment of a cardiac drug delivery system. Herefixation mechanism consists of a needle 484 with apertures 486 thatpenetrates the myocardium and is held in place by barbs 466. In achronic implant barb 466 may be composed of either a rigid metallicalloy or a biodegradable polymer. If a biodegradable material is used,long term tissue attachments will maintain fixation with the heart, andthe barb 466 will not cause undue trauma should the drug delivery systemneed to be explanted.

In addition, FIG. 4 shows a multilumen catheter and valve system for thefilling of reservoir 462. Agents may be delivered down the fluid pathdefined by filling lumen 452 in bilumen tubing 450 such thatunidirectional check valve 456, shown here as a ball check valve, isopened allowing agents to flow through lumen 458 of tube 460 and out thedistal end of tube 480. The ball check valve has a sphere in a generallyconical tube which allows unidirectional flow by obstructing the smallerdiameter fluid pathway to reverse flow and not obstructing the largerdiameter circular pathway of the open flow direction. In variousembodiments it could be replaced with a reed check valve, a hinged platecheck valve, or the equivalent. After the reservoir is filled, the fluidwill open check valve 472 and flow out clearing lumen 468 in bilumentube 450. This filling action will force ball check valve 470 closed.After filling, the remaining agent in the bilumen tube may be cleared bydelivering sterile distilled water, which may contain anticoagulantssuch as heparin to assure long term patentcy of the catheter lumens,down clearing lumen 468. This clearing fluid will force check valve 472closed, and check valve 470 open such that agents may be flushed fromthe bilumen tube and replaced with the distilled water or other flushingagents. If the system is chronically implanted, such a bilumen tube andseries of valves would allow one to fill the reservoir 462 and clear thebilumen tube 450 after implant. Further, because the distal end of thetube 480 allows for filling of the reservoir 462 from the distal end,agents may be changed merely by filling via filling lumen 452 which willforce the existing agents out through proximal reservoir exit 474,through valve 472 and clearing lumen 468. If the proximal end of such abilumen delivery system were connected to a dual port subcutaneousreservoir (not shown) agents would be injected into one port whilewithdrawn from the second port.

In this delivery catheter, the distal housing also acts as an osmoticdelivery system with semi permeable membrane 496, hydrophilic salt oragent 476, and flexible polymer barrier 464 allowing for controlleddelivery of agents over a period of time. After the expiration of theosmotic energy source, agents may be delivered via the fluid pathway byan external pumping means if desired. The valve housing 454 houses thethree unidirectional valves 456, 470, and 472, and provides tubefittings 488 and 490 for connection to the bilumen tubing. This valvehousing 454 is also attached by a crimp 494 to the coil 492. Thiscomplicated structure would be assembled from the separate componentsand combined. Separate valves could be fit into openings in a simplermetallic form, and the whole could be mechanically and hermeticallyattached to the rigid osmotic pump housing 478. Rigid support 482 isrigidly attached to needle 484, and may also have structural elementswhich enter into the region of the hydrophilic salt, and possibly attachto the valve housing 454. It should be clear that many variations arepossible.

FIG. 5a shows a partially sectional view of an embodiment where amembrane or rate controlling barrier 506 stands between the agentreservoir 502 and the apertures 518 in the proximal end of the deliveryneedle 520 which would allow the agents to be delivered to the distalend of the delivery needle 524, and through the apertures 522. It isclear that the needle could be replaced with a hollow helical deliverydevice as shown in FIG. 1c if so desired. Included here is optionalcontrolled release structure 508 for providing chronic delivery ofagents to the implant site. As this agent diminishes, new agents can beprovided through the connecting tube and check valve 402, such that rateof release is governed by control barrier 506. Barrier 506 is shown herewith substantial thickness, but it could be formed of a simple membrane,a membrane reinforced with a substantially porous structure, such as alaminate of expanded polytetrafluoroethylene (ePTFE), or any otherstructure which could be used to govern the rate of drug delivery to theside of the barrier connected by a fluid pathway to the tissue to betreated. The design of the control release barrier would be customizedfor the agents to be delivered and may be intentionally designed tospecify a rate of delivery substantially different from that which theoptional control release structure 508. Needle plug 516 prevents flowthrough the needle lumen, while maintaining a rigid axial support, andcould be formed of an inert polymer or metallic material. Rigid support510 acts to support axial location of needle 524 and may be a mechanicalbase for the helical fixation means. Controlled release structure 508could be composed of a macromolecular controlled release matrix such asEVAC housing a growth factor such as TAF, bFGF, or aFGF.

In another preferred embodiment of FIG. 5A, controlled release structure508 would be left out and the space would be filled with pharmacologicalagents and act as a reservoir for acute delivery immediately afterimplantation. The fluid path for subsequent agents would then passthrough tubing 104, through check valve 402, through proximal needle 512and through proximal apertures 514 into agent reservoir 502, containedby drug reservoir housing 504. The fluid agent must then pass throughrate control barrier 506 to be in contact with acute fluid reservoir508.

In other embodiments of FIG. 5, the control barrier 506 could beelectrically activated to allow rapid delivery of positive pressure andagent delivery from one side to the other. In this electricallyactivated embodiment, the optional control release structure or acutereservoir 508 could merely deliver agents acutely to preserve theviability of the fluid pathway for the time when therapy is deemednecessary. Acute delivery of antithrombolytics and antiinflamitoryagents would limit blockages and tissue inflammation resulting from theimplantation of the structure in the heart wall and improve the abilityof a transient system to deliver agents quickly and effectively to theregion within the tissue. An electrically controlled barrier could befashioned much like any electrically controlled microvalve.

FIG. 5b shows a partially sectional view of the drug delivery systemdescribed in FIG. 5 which incorporates a separate stylet lumen 552within the same catheter body 550. Such a stylet lumen will allow for aremovable wire element that will allow the implanting physician tocontrol the shape of the device to guide it to the appropriate site.This additional lumen 552 allows the drug delivery tubing to travel thelength of the coil in its own lumen 554. Although shown here as acontinuous part of catheter body 550, stylet end stop 556 would mostlikely be attached as a separate component. FIG. 5c is a cross sectionalview of bilumen catheter body 550 which shows the diameter of styletlumen 552 to be substantially smaller than lumen 554. These lumens maychange depending upon the requirements for different applications. Suchan additional lumen for stylet use could easily be combined with any ofthe drug delivery systems presented here. This additional lumen willprevent the lumen of the drug delivery tubing 104 shown in thesedrawings from getting obstructed with body fluids during stylet use,prevent damage to tubing 104 by the stylet, and allow the materials ofboth stylet and tubing 104 to be chosen without regard to therequirements of the other.

FIG. 6 shows a partially sectional view of one preferred embodiment of asubcutaneous reservoir 626 and a drug delivery catheter 628 which may beconnected to the proximal end of the delivery catheters shown.Subcutaneous reservoir 601 consists of a housing 602 whose reservoir 606may be filled with a fluid pharmacological agent. The agent isintroduced into the subcutaneous reservoir 601 by transcutaneousinjection into the reservoir 606 through the polymer injection barrier604. This barrier is typically composed of silicone rubber such that itcreates a seal after removal of the filling needle. In addition, thehousing 602 is typically constructed of titanium, polyurethane, or otherknown rigid biocompatible and non-reactive materials.

FIG. 6 provides a means for connecting the drug delivery catheter to asubcutaneous reservoir, constant pressure pumping means, or transientdelivery automatic infusion pumps. Subcutaneous reservoir 626 has a port610 which accepts the proximal end of delivery catheter 628 such thatthe region of separation 622 between the crimp structure 620 andproximal end of the jacket body 614 is completely within port 610. Thiswill prevent fluids from entering the separation 622 which allows thecoil and inner tubing 624 to rotate relative to the jacket body 614 foradvancement of fixation structure 616 and needle delivery system 618.After the proximal end is inserted into port 610 of subcutaneousreservoir 626, a set screw may be advanced within threads 608 to securethe catheter in position by applying force to pin 612. This set screwconnection to the pin is common in devices used to deliver electricaltherapy to the heart, and could be used to perform an electricalconnection to the fixation means 616 or needle 618 in order to sense theelectrical activity of the tissue. This electrical signal could bemonitored by devices with algorithms similar to those designed todeliver electrical therapy to the heart, accept that instead ofelectrical therapy they introduce pharmacological therapy.

FIG. 7 shows another embodiment of an acute drug delivery system. Thecatheter body 702 houses a lumen 704 for fluid transport of therapeuticagents and a lumen 706 for stylet use during implantation. Lumen 704travels the length of the delivery catheter and connects to needledelivery structure 714. During implantation through the vasculature,blood soluble coating 710 completely protects the vasculature from thesharp elements of the helical fixation means 712 and the needle deliverystructure 714. Blood soluble coatings such as sugars may be used. Afterthe appropriate heart chamber is accessed, the physician must wait forthe coating 710 to dissolve. The coating may be combined with a radioopaque material such as barium sulfate to identify better when this hasbeen accomplished. After the coating 710 has dissolved, the physicianimplants the helical fixation means 712 by rotating the entire catheterabout its own axis. Torque is delivered from the catheter body 702 tothe helical fixation means 712 by the embedded portion of the helicalfixation means 708. This embedded region can easily be manufacturedusing molding and bonding technology. The principle advantage of thisdevice is the small cost of manufacturing such a simple design with nomoving parts.

FIG. 8 shows a hollow helical fixation means 802 with apertures 804along its length. Sectional view of FIG. 8A shows the hollow crosssection 812 to be filled with a second material 810. Second material inthe preferred embodiment is a controlled release polymer matrix filledwith a therapeutic agent for extended delivery of agents throughapertures 804 in helical fixation means 802. In one embodimentcontrolled release matrix is comprised of silicone rubber and the agentto be delivered is lidocaine. In another embodiment the agent may beamiodarone HCL. In another embodiment, the controlled release matrix isEVAC and the agent is aFGF. Other variations are also possible. Afterimplantation of the structure within the heart wall by penetration ofhelix tip 808, the rest of the helix is rotated such that all apertures804 are within the tissue. Agents then migrate from the controlledrelease matrix to the tissue in which it is implanted. Such a controlledrelease matrix filling of the hollow core which penetrates the heartcould be pursued with other penetrating structures as well.

FIG. 9 shows a drug delivery system with VEGF in an EVAC matrix 908housed in a reservoir defined by cylinder 906, and ends 904 and 914. Inthe preferred embodiment, these are non-permeable, although in otherembodiments permeability may be desirable. End 904 acts both to transmittorque to helical fixation means 916, but also as a stop for a stylet(not shown) which may be used during implantation down the coil lumen902. After implantation of the drug delivery catheter, body fluidsmigrate through apertures in distal needle 920 and into reservoirthrough proximal needle 912 and dissolve pharmacological agents in acutedosage 910 which may be present to counter inflammation associated withimplantation. Over time, growth factors are delivered via needle 920 toa depth within the heart. Note that the absence of a tube for agentdelivery enables stylet use during implantation. In variations on thisembodiment, other controlled release means could be housed within a semipermeable structure that would allow increased fluid transport to assistin delivery of agents through needle 920 to a depth within the heartwall.

FIG. 10a shows another drug delivery catheter in which agents may bedelivered transiently to a depth within the tissue. Here, helical coilconsists of four co-radial wires 1000 a, 1000 b, 1000 c, and 1000 dwhich are electrically isolated from one another by a layer ofinsulation. The electrical insulation allows a current pathway to bedefined which allows current to flow through electrical connection 1018of wires 1000 c and 1000 d and into Nitinol thermally activated shapememory ribbon 1020, which wraps around flexible polymer barrier 1010 andis also shown in cross sections 1006, 1024, and 1008. Current flowingthrough Nitinol ribbon 1020 completes its circuit to wires 1000 a and1000 b at electrical connection 1002 to torque delivery structure 1004via conduction through connection to support structure 1012 which iselectrically connected to needle 1028. Insulating structure 1032separates the two electrical connection regions on structure torquedelivery structure 1004 and allows current to pass through ribbon 1020.If the electrical resistance of the nitinol is relatively high, ohmicheating may prove to be sufficient to cause a constricting shape changeupon the flexible polymer barrier 1010. Contained within flexiblepolymer barrier 1010 is a partially porous polymer controlled releasematrix structure 1022 such as silicone rubber containing lidocaine,which upon compression by the nitinol ribbon, will force agents out ofthe controlled release matrix 1022 and through the needle 1028 withinthe reservoir 1026 and out the needle 1016 into the heart.

FIG. 10b shows another transient drug delivery structure in which areservoir contains a fluid whose vapor pressure provides the energy todeliver therapeutic agents. As in FIG. 10a, the different filars in thehelical coil, such as filar cross section 1068, are electricallyinsulated from one another such that two independent electricalconnections may be made at crimp 1050 and crimp 1072 which are separatedfrom each other by electrically insulating barrier 1070. The electricalconnections made at crimp 1050 and 1072 have an electrical path betweenthem which is defined by resistive heating element 1052 which passesthrough reservoir 1056. Within reservoir 1056 is a fluid gas mixturewhich provides a constant pressure at human body temperature via plate1058 to the drug matrix 1060. If drug matrix 1060 is a substantiallyporous controlled release matrix, the pores surrounding the matrix willbe filled with relatively high concentration of agents in fluids. Aselectrical energy is delivered down the two independent electricalconductors to resistive heating element 1052 and increase thetemperature of the fluid within reservoir 1056. As reservoir housing1066 and support structure 1064 are rigid and non-compliant, this willincrease the pressure within reservoir 1056, cause expansion of bellows1054 and apply pressure to the controlled release matrix 1060. This willforce the concentrated fluid from within the porous controlled releasematrix into proximal end of needle delivery system 1074 and out throughthe distal needle into the heart wall. Such vapor pressure energysources have been used in infusion pumps such as Infusaid's infusionpump (Norwood, Mass.). However, it is not known if such a system hasever been implanted on a catheter, or whether the vapor pressure systemhas provided for a thermal element to increase the temperature withinthe charging fluid and thus the pressure delivered transiently. Inaddition to the porous matrix, there is a soluble anti-thrombogenic andanti inflammatory agent for acute in acute dosage form 1062 whichsurrounds proximal length of needle 1074, while still leaving the endfree for agent administration. Such acute dosage forms may be veryuseful for guaranteeing the long term outcome of such controlleddelivery systems by minimizing the response of the tissue to the traumaof implantation.

A method for delivering therapy using a combined drug delivery ablationcatheter proceeds as follows. Initially the arrhythmogenic site islocated using techniques common to those in the field of cardiacelectrophysiology. The delivery system is inserted into the appropriatesite within the heart by the internal or external jugulars, cephalicvein, subclavian vein, femoral artery or other vascular delivery routes.Then, the drug delivery structure is implanted at the arrhythmogenicsite to supply an appropriate agent for altering the local conductionproperties. After implantation, agents are delivered and the effect onthe arrhythmogenic site is evaluated by electrical techniques such asmapping. If the location is appropriate, and the agents appear toterminate the critical arrhythmia, RF energy is delivered to the tissueby way of the same structure used to deliver the agents to the heart. Ifthe position is inappropriate and the local pharmacological agents donot correct for the arrhythmia, the device is repositioned, and theprocedure is repeated.

A method for transient treatment of supraventricular arrhythmias using achronically implantable transient drug delivery catheter proceeds asfollows. After electrophysiologists have specified the appropriateregion for implantation based upon the patient's cardiac electricalaction, a catheter is implanted at this site to deliver antiarrhythmicagents at a depth within the heart transiently, as well as to sense theelectrical activity near the device. The catheter is then connected toan external controller and power source, which determines suitability oftherapy and delivers energy to a device such as those described in FIGS.10a and 10 b for transient delivery of pharmacological agents, or to adevice such as that shown in FIG. 1c coupled to a proximally locatedpumping means. The device then senses cardiac activity through thesurface of the drug delivery structure. When the heart experiences anarrhythmic event, the controller identifies the event and activates theenergy source which delivers the drug to the heart. This drug modifiesthe selected area of tissue and either terminates the arrhythmia, orsubstantially reduces the magnitude of the required electrical therapy.If the arrhythmia does not terminate, the pump may deliver a secondarydosage, or trigger an external electrical therapy device. If noarrhythmia is sensed. The device is maintained in monitoring mode.

FIG. 11 shows a sectional view of the heart 1101 with a triple cathetersystem passed retrograde across the aorta 1105 and into the leftventricular chamber 1115. Guide catheter 1120 is placed across thetricuspid valve and a steerable guide catheter 1125 is advanced throughits lumen in order to target a region of the heart wall 1110 fordelivery. Within the steerable guide catheter 1125 is drug deliverycatheter 1130. Once oriented towards a region of the heart wall 1110such as the septal region 1140 shown, the centrally located drugdelivery catheter 1130 is advanced into the heart wall 1110 and fixed tothe heart tissue by means of the fixation element 1135. In the case ofthe hollow helical fixation structure 1135 shown, an element in thecentrally located drug delivery catheter 1130 must be rotated in orderto advance the fixation helix into the heart wall. The catheter systemused to implement the inventions described herein can be provided in avariety of configurations permitting delivery and deployment of thefixation tip within the heart. In one alternative embodiment, the outerguide catheter is not used, and only the steerable guide catheter anddrug delivery catheter are used. The drug delivery catheter may be anon-steerable catheter within a steerable guide catheter. In a thirdembodiment, a single steerable drug delivery catheter is used, whichalso allows for deployment of a distally located penetrating structuresuch as the helix 1135 shown, with or without a guide catheter. In afourth embodiment, the single catheter system may be preformed to effecta particular shape within the heart, while allowing deployment of thedistally located penetrating structure which is directed to the desiredsite in the heart by the preformed shape of the preformed distal tip ofthe drug delivery catheter. In a fifth embodiment, a dual cathetersystem is used in which the guide catheter is pre-shaped to effectdelivery to a certain location, and the drug delivery catheter isdelivered from within the pre-shaped system. The preformed shapes arechosen to facilitate preferred orientation of the distal tip of thecatheter system in apposition to a desired site of treatment (i.e., thedistal opening 1136 is facing treatment site 1137 in the septal wall)when the catheter distal tip is at rest within the heart.

The use of these various systems is similar, but there are subtledifferences. For example, in the case where there is an outer guidecatheter which is separate from the centrally located drug deliverycatheter, the catheter will likely be passed over either a guidewire, orother pre-placed catheter system to gain access to the ventricle. In thecase where the system is a single catheter with a deployable infusionelement, the catheter can be designed such that the distal curve enablesthe catheter system to be prolapsed across the aortic valve or steeredthrough and eliminates the need for guiding wires and guiding cathetersto access the heart chamber for some physicians. In the cases whereconcentric catheters are used, there will be concern that blood mayenter the very thin space between the catheters, and catheters would bedesigned with infusion ports to enable the continuous flushing of thespace between these catheter systems. Further, these catheter surfacesmay be coated with heparin to reduce their thrombogenicity and potentialfor embolic thrombus formation.

Although ultrasound, radio-opacity, electromagnetic signals, and thelike may be used to position the system within the myocardium withtechniques described elsewhere, the location of the infusion system oncefixed to the tissue is preferentially confirmed visually by flushing theheart chamber with a contrast medium and viewing the radio-opaquepenetrating element and catheter body relative to the boundaries of theheart wall. In many cases this will be performed by delivering contrastthrough a guide catheter, but adjacent separate catheters, as well asdistally located contrast lumens within the drug delivery catheter areviable routes for contrast medium to egress into the heart chamber wheredelivery is desired. Contrast could also be delivered down a drugdelivery lumen and into the myocardium to confirm device position,evaluate pharmacokinetics, or visually observe the lymphatic transportaway from the region.

The drug delivery catheters with distal fixation devices arebeneficially combined with the features described in the followingfigures, which enable confirmation of position of the catheter andcontrolled injection of a desired dose of therapeutic agent into theheart wall. The catheter system that has its drug lumen pre-filled witha passive agent such as saline or Ringer's solution to be positionedprior to delivering the therapeutic agents. Once positioned, thetherapeutic agent is delivered, and is then followed by a small volumeof the passive agent. This subsequent delivery of passive agent willclear the dead space in the catheter, ensuring injection of the entiredose (as measured by the catheter fluid volume) and promote advancementof the therapeutic agent into the myocardium.

FIG. 12 shows a drug delivery catheter with fixed distal penetratingelement for implantation within the heart. Catheter handle 1202 is shownwith its outer casing removed to illustrate the position of the twosyringes 1204 and 1206 within the handle. The syringe plungers 1230 areslidably disposed within the syringes, and are operable from outside thecatheter handle with the thumb-slides illustrated in FIG. 13. Prior todelivery of the catheter distal tip 1231 into the heart, the smallsyringe 1206 is filled with therapeutic agent and large syringe 1204 isfilled with passive agent. Syringes 1204 and 1206 are filled in thetraditional manner and are then connected attached to distensible tubing1206 and 1207 with leur fittings 1213 and laid into position within thecatheter handle 1202. Prior to insertion of the catheter into the body,the therapeutic agent syringe 1206 is flushed, with stopcock 1210rotated such that therapeutic agent syringe may flush any air within thesyringe into distal drug delivery tubing 1212. Then, also prior todelivery into the body, the stopcock 1210 is turned so that passiveagent syringe and its distensible tubing 1208 are aligned in fluidcommunication with the drug delivery tubing 1212. The drug deliverytubing may be flushed for a full measure of the catheter drug deliverytubing, until the entire tubing length and the distal penetratingelement's dead space has been flushed of any air within. The dead spaceis the volume of the fluid pathway between the reservoir of therapeuticagent and the discharge point at the distal tip of the catheter.

The dead space in many catheters will be equivalent to the amount ofdrug in a proximally located reservoir that is not effectively deliveredto the tissue. This dead volume will cause inaccuracy in dosing, whichcan be important when small volumes are delivered. It is desirable tohave the dead space be small, and the preferred inner diameter of thedrug delivery tubing is preferably less than 0.03 cm (0.012″). (In acatheter of 100 cm length, this amounts to a dead space volume of 0.07milliliters, and in a catheter of 135 cm length, it results in a deadspace of about 0.09 milliliters. Preferably, the volume of the deadspace is in the range of 0.05 ml and 0.25 ml.) Control of the dead spacevolume is important to provide good control of the drug dosage into theheart.

One way to eliminate the issue of dead space and dosing errors is tohave a post delivery flushing method. Syringe 1204 is larger in diameterthan syringe 1206 such that an equivalent displacement of each syringewill result in more fluid being dispersed from the larger syringe. Inthis way, therapeutic agents may be delivered in volumes less than thatof the dead space and followed up by a flushing infusion that will fullyclear the remaining therapeutic from the catheter body. This flushingprocedure has the advantage that it enables small volumes of agents tobe redistributed to some degree by a passive flushing medium such asbuffered saline. Additionally, the system may be flushed and filled withthe flushing fluid from the second syringe prior to injection oftherapeutic agent from the first syringe, so that doses of therapeuticagent which are smaller than the volume of the dead space may beaccurately delivered, and expensive therapeutic agent need not be usedmerely for flushing the system of air bubbles. After the system isinitially flushed and filled with the fluid from the second syringe, apredetermined dose of the therapeutic agent may be injected from thefirst syringe into the dead space of the tube 1212. The injectedtherapeutic agent is then fully delivered upon being flushed from thedead space by a second injection of the flushing fluid from the secondsyringe.

The components of the fluids stored in each syringe may be adjusted toprovide additional benefits. Dual syringes, coupled to the securefixation element, provide means to infuse the tissue with one agent, andfollow it with delivery of a second potentially synergistic agentwithout having interaction between these two agents occur beforedelivery. The second syringe can be loaded with an agent which activatescomponents of the therapeutic agent stored in the first syringe byaltering the physical and chemical properties of the first agent.Delivery of the activating agent to exact site is thereby accomplishedwithout manipulation of the catheter system. One example of such a usewould be to deliver liposomal preparations from the first syringe, inwhich liposomes encapsulate a therapeutic compound and protect thetherapeutic compound from degrading interaction with the cathetertubing. The liposomes are typically stable within a narrow range of pH,but which are unstable exposed to a different pH. The second syringe canthen be loaded with a fluid having a liposome destabilizing pH. Whenthis liposome destabilizing fluid is injected, it serves to clear thedead space of the therapeutic agent and interacts with the liposomes inthe first agent to break down the liposomes and release the encapsulatedtherapeutic compounds simultaneously or shortly after the injection ofthe therapeutic agent into the heart. In this way, the encapsulatedagents are released only after they have been deposited into the tissueand have been flushed with a destabilizing solution which destabilizesand breaks down the liposomes which encapsulate the therapeutic agent.Also, a contrast medium may be used as the flushing medium provided inthe second syringe, so that flushing will also serve to mark thelocation at which the therapeutic agents were delivered. Marking theinjection site with contrast agent injected into the wall of the heartfacilitates subsequent placement of the infusion needle for additionalinjections of therapeutic agents.

A luer adapter 1201 for delivering contrast medium is present on theback of the catheter system in this design so that contrast may bedelivered through the catheter body tubing 1214 in the space 1230surrounding the drug delivery tubing 1212. This luer fitting isconnected to contrast tubing 1203 which communicates into the Y-adapter1205 with a suitable bonding or potting agent. The Y-adapter also isbonded to drug delivery tubing 1212 at the proximal end of the drugdelivery tubing and to catheter body tubing 1214 at its proximal end.When contrast agent is injected into the leur fitting 1201, it flowsthrough the space between the drug delivery tubing and the catheter body1214. Small holes may be provided at the distal end of the catheter toenable the contrast to escape, or the penetrating element such as helix1224 may be fixed over a hollow cylinder 1218 attached to catheter body1214 by adhesive or other bonding material 1226. Here therapeutic orpassive agents are delivered through hollow helical needle 1224 fromdrug delivery tubing 1212 and contrast is delivered through the annularlumen 1252 between the catheter body 1214 and the drug delivery tubing1212, then through cylinder 1218. A pressurized source of passive agent,such as saline solution, may be connected to the leur fitting 1201 witha Y-adapter 1251 so that the catheter body may be flushed continuouslyto prevent the possibility of blood entering between the drug deliverycatheter and the catheter body catheters, clotting, and thereafterbecoming dislodged into the blood stream. Infusion solutions such asheparinized saline are preferred for this. In one embodiment theinter-catheter space (that is, the annular space or lumen 1215 betweentube 1212 and catheter body 1214) could be connected to a gravity fed orpump fed fluid source such that the infusion would be continuous duringthe procedure. Additional branches could be used such that the cathetercould be continually flushed and contrast could be delivered transientlyfor performing ventriculograms and the like to confirm catheterposition.

FIG. 13 shows an enlarged view of the catheter handle shown in FIG. 12with the cover 1301 in place and the syringe plungers in place onthumb-slides 1306 and 1302. Stops or detents 1312 a, 1312 b, and 1312 care provided on the outer surface of the cover, in partially obstructingrelationship to the thumb slides so that, when the thumb-slides arepushed distally, they encounter noticeable resistance upon meeting anyone of the detents, but may be pushed past the detents with additionalforce applied by the operator of the device. This enables the operatorto inject predetermined volumes of fluid (corresponding to the volume ofthe syringe cleared by movement of the syringe plunger between thedetents) by pushing the thumb-slides between detents. These stops may beeither visual marks, or they may be physical barriers requiring moreforce to overcome, or an adjustment to be made before passing. Prior toinjection, the stops may be moved along track 1314 such that they can bevaried and effect a different dosing regime for a different patient ordifferent agents, if so desired. Slides 1306 and 1302 advance in tracks1308 and 1304 and engage the plungers, so that the plungers move withthe thumb-slides, thereby displacing fluid from the syringes and intothe drug delivery tubing. (The cover 1301 may be snapped in place afterpositioning the syringes internally, and may be hinged as shownschematically along line 1318 so that it lifts for syringe placement. Ahole 1316 is shown to allow access to the stopcock within, but analternative structure on the cover 1301 could be placed to engage thestopcock.)

FIG. 14 shows the two piece proximal handling mechanism for druginjection and manipulation of the helical coil attached to drug deliverytube 1212 and steerable guide catheter 1412. FIG. 14 shows the drugdelivery catheter handle 1202 and steering handle 1450 in an elevationalview. The drug delivery handle has a cylindrical distal end 1404 tofacilitate engagement with the cylindrical bore 1451 of catheter handle1406. The drug delivery catheter may be rotated relative the steeringcatheter handle, and can be longitudinally advanced and retractedseveral centimeters while the cylindrical distal end is engaged insidethe cylindrical bore. The guide catheter 1412 is steerable, and has atleast one pull wire 1416 which is pulled around pulley 1414 and overrotation knob 1410 where it is attached by block 1418. The pull wire isdisposed within the side wall of the guide catheter and secured to theguide catheter body at the distal end of the guide catheter, such thatrotation of knob 1410 will pull the pull wire 1416 and effect adeflection of the distal tip of guide catheter 1412 (not shown). Anadditional pullwire 1417 may be provided on the opposite side of thecatheter body to provide positive control of the distal tip curvature,rather than relying on the resilience of the catheter tip to effectstraightening. In one embodiment, the drug delivery catheter 1408 isplaced in the guide catheter prior to steering the guide catheter withinthe heart in order to prevent the localized bending on the hollow guidestructure from causing a kink to form in the distal tip of the hollowcatheter. The drug infusion catheter acts to support the guide catheterduring the steering process. Such a system may be steered across theaortic valve, or deflected 180 degrees upon itself to prolapse acrossthe valve. The more traditional approach of advancing the steerableguide over a preplaced guide wire, and then following it with theinfusion system is also appropriate.

FIG. 15A shows a means for stabilizing the distal portion of the guidecatheter to prevent localized buckling. To control steering, it isdesirable to have a catheter that will not buckle and which also has alower bending rigidity in the plane in which the distal structure is tobend. It is also desirable that the distal region of the catheter not besubstantially stiff. Braided catheter body 1502 is bonded to thebendable region through standard catheter joining techniques such as anovermolded lap joint. The deflecting region of the guide catheter 1530comprises a flexible and easily bendable tube 1504 with a coil 1506disposed coaxially within the tube shown in cross section in FIG. 15a15A and in an elevational view in FIG. 15B. Coil 1506 will prevent thestructure from buckling locally. The pullwires 1416 and 1417 are fixedat their distal ends to the distal end of the coil 1506, or to a pointin the bending section wall, so that proximal tension on either pullwirebends the bending section. An alternative solution would be to place anumber of hoops in the distal portion of the catheter that can moverelative to one another. To create the lowest bending rigidity in thedesired plane of bending, bending ribbons 1508, 1510, 1520, and 1522 areplaced such that their long axes are in the plane perpendicular to thedesired plane of bending as defined by the plane in which both pullwires lie. The ribbons may be fixed to the helical coil 1506, or theymay rely on adhesives to secure and define their positions within thecatheter body. The ribbon and helical coil may also be formedsimultaneously by molding them out of higher durometer polymermaterials, although they are metallic in their preferred embodiments.FIG. 15B shows that the two pull wires 1416 and 1417 may be attached tothe distal portion of these ribbons or even to the distal portion of thehelical coil. Again, connecting means are likely to involve crimping,brazing, welding, and combinations of these. Pull wire may also bereplaced with a pull cable in embodiments where multiple flexures of thebending element may introduce fatigue. FIG. 15C is a distal end view ofthe catheter which shows the two ribbons 1508 and 1510 positionedadjacent to the two pull wire lumens 1512 and 1514 (which housepull-wires 1416 and 1417), being disposed within the catheter within theplane established by the two pullwires. FIG. 15D shows a modification ofthe placement of the bending elements in relation to the pull-wires. Thetwo pull wires 1416 and 1417 are again located in the catheter bodywall, defining a plane in which the two pull wires lie, with ribbons1520 and 1522 being disposed in the plane intersecting the pullwireplane at an angle of about 90 degrees and intersecting the center of thecatheter. The preferred bending plane 1530 of the ribbons is parallelwith the plane 1531 in which the pullwires lie. FIG. 15E illustratesanother embodiment in which four ribbons are placed within the catheterit body wall, distributed at 90 degree intervals around thecircumference of the catheter body wall, with the preferred bendingplanes 1530 of each ribbon parallel to each other, and two pull wiresare disposed within the catheter body wall, 180 degrees apart from eachother and within the plane 1531. FIG. 15F shows the cross section 15F ofFIG. 15A, illustrating the braided catheter body tubing 1502 and showinglumens 1514 and 1512 which enable the pull wires and cables to be pulledby the hand piece with minimal friction.

FIG. 16 shows a steerable guide catheter with two distally locatedbending segments 1602 and 1604. Bending segments 1604 and 1602 areformed of a slotted hypodermic tube such as that described in U.S. Pat.No. 5,322,064. These two bending elements are formed from the same pieceof hypotube with the slots of segment 1602 made at 90 degrees angle fromthe slots in segment 1604, thereby comprising two sets of slotsorthogonally arranged on the circumference of the tube. The hypodermictubing is covered with thin walled polyolefin material (not shown) andtipped with a soft tip low durometer Pebax or silicone material 1650 atthe distal tip. Pull wires are affixed to the tubing by wrapping themaround small pins and passing the pull wires through holes in the distalregions of each bending element. Bending segment 1602 has a single wire,shown in the cross section of FIG. 16a, disposed within the lumen 1619in underlying catheter body 1616 with the slotted hypodermic tubing 1618coaxially overlying the catheter body 1616. The pullwire is anchored atthe distal end of the ending segment so that proximal movement of thepull wire causes bending of the segment. The pullwire lumen is orientedat the circumferential center of the cutaway slots, so the bending forceis applied along the plane in which the slots have created a bendingpreference, (that is, the slots are perpendicular to the plane ofbending, and establish the preferential bending plane, and the pullwireis located in the preferential bending plane, on the same side of thecatheter as the slots. Segment 1604 has an additional pull wire lumen1621, shown in the cross section of FIG. 16b, the pull wire (not shown)which affixes to the hypodermic tubing near the distal end of segment1604 and enters through the hypodermic tubing 1618 to enter in lumen1621 in Pebax tubing 1616. The pullwire 1621 is operable from theproximal end, and translates tension on the pullwire into bending ofsegment 1614 in the plane perpendicular to the length of the slots. Thelumen 1621 is orthogonal, or located 90° from the lumen 1619 relative tothe circumference of the tube, so the tip of the catheter can be bent todifferent degrees in two planes established by the pull wires and thecentral axis of the catheter. The tubing 1616 runs the length of thecatheter and passes within proximal braided catheter shaft 1624, asshown in the cross section of FIG. 16c. Pebax may also be lined withPTFE for lubricity in advancing catheter elements down its length. Thecatheter shaft 1624 may be formed with a number of sections such thatthe durometer changes from high durometer to low durometer resin nearthe distal end of the catheter. The braid can also be varied to affectstiffness and torqueability and in the preferred embodiment is made with0.0025 inch (0.06 mm) diameter stainless wire with 45 Pics per inch (20pics per cm). Pull wires connect to proximal pull wire knobs 1614 and1610 which are disposed one atop another to facilitate ergonomic controlof dual axis bending at the distal end. This guide catheter is moldedwith luer 1612 in place in proximal handle 1612 such that this guidecatheter can be used for performing coronary angiograms, leftventricular angiograms, and as a guide for placing other devices andfluid agents within body lumens. In addition to its ability to accessthe heart, this dual axis steerable guide catheter has many advantagesas it may also be slightly modified to enable docking of an infusioncatheter handpiece.

FIG. 17 shows a steerable guide catheter similar to the device of FIG.16 modified by the addition of a docking infusion catheter. Here,infusion catheter handpiece 1710 enters the proximal handle 1714 of thesteerable guide which has a narrowing channel 1716 for enabling theadvancement of an infusion catheter after the guide has been advanced toits appropriate location within the body over a guidewire. Thefunnel-shaped narrowing channel 1716 prevents the infusion catheter 1718from catching and buckling during its advancement into the lumen of theguide catheter. The cylindrical body of the infusion catheter proximalhandle 1202 fits into the cylindrical bore of the steering catheterhandle. The dual syringe system of this figure is similar to the systemof FIG. 12, but has been modified so that each syringe connects to aseparate lumen in a dual lumen tube 1750 which traverses the entirecatheter length. This bilumen tubing connects directly to the fixationhelix 1704, as shown in FIG. 4. Here the dead space for each tubinglength remains, but precision of the interaction of the two agents maybe controlled at the distal end of the catheter, to achieve theadvantages of flushing and interaction already described. In FIG. 17,the distal helix infusion element is shown to be larger than the lumenavailable within the catheter body, and to taper to a smaller diameterwithin the catheter body. Such a system cannot be passed from one end ofthe catheter to the other, but enables the diameter of the catheter tobe kept to a minimum. In such a system, the larger fixation structure isessentially garaged in the larger body tubing of the guide catheter tip1650 or distal bending segment 1602, and can be advanced and rotated byadvancing and rotating the cylindrical infusion handpiece 1710 withinthe guide handpiece 1714. Once advanced just a bit from its garage,space exists between the guide catheter inner lumen and the infusioncatheter outer diameter for flushing of contrast agents to improvevisualization of the catheter position. Such infusions enable very clearvisual confirmation of the engagement of a fixation element with anyregion desired within the heart when viewed under bi-planar fluoroscopy.

FIG. 18 shows a schematic of the helical infusion system being used forpercutaneous transmyocardial revascularization (TMR). The helix 1804,which may be delivered to the endocardial spaces of the heart with anyof the previously described catheters and methods, is advanced to adepth within the heart tissue, for example the left ventricle wall 1816,is used to create helical pathways of damage within the heart tissue.Cross-section of the helix path in the heart tissue would reveal areas1808 of damage that corresponds to the needle track. These areas ofdamage may be beneficial in that these small injuries will triggerendogenous repair mechanisms and reduce angina. Although others arecreating straight channels in the heart using lasers, radiofrequencyenergy, or mechanical coring techniques these systems are lessdesirable. The helical system shown has the distinct advantage that itmaximizes the volume of tissue effected, while minimizing the damagethat is introduced (particularly limiting damaged to the endocardium forany given amount of myocardial damage). Simultaneously, damaged tissue1808 is interleaved with undamaged tissue 1810 through the penetrationprocess. This allows more interaction of healthy tissue with the factorsinvolved in the tissues response to injury. Further, because the helicalpathway through the tissue is more quickly self-sealing than thestraight puncturing devices currently used, it has large benefits aswell. The helical pathway and screw-action required for TMR woundingprevents puncture of the heart and bleeding into the pericardium. Theself-sealing helical pathway greatly reduces the risk of lifethreatening pericardial tamponade being caused by blood entering thepericardium, and also greatly reduces the potential of therapeuticagents 1818 previously or subsequently deposited in the myocardium fromleaking into the heart chamber and entering the systemic circulation.Reduced leakage is important to ensure that dosing is appropriatelydelivered, and critical to prevent the possibility of embolic eventsoccurring when controlled release structures larger than 8 microns indiameter are delivered to the tissue. Agents 1818 in the preferredembodiment are microspheres containing angiogenic agents with a minimumdiameter of 30 um in diameter.

A cardiac surgeon performs TMR according to FIG. 18 by inserting thehelical needle into a chamber of the heart, for example the leftventricle, and then operating the helical coil to screw it into theheart wall. The surgeon may then inject a small volume of contrast agentthrough the helical coil into the heart wall to mark the position of thewound. The contrast agent may be incorporated into degradablemacromolecules, microspheres or other large molecules described hereinto inhibit quick migration within the myocardium and back-leakage fromthe wound or needle track. The surgeon may then inject a therapeuticagent into the wound, through the helical coil. Again, the therapeuticagent may be incorporated into macromolecules, microspheres or otherlarge molecules to prevent excessively quick migration and back-leakageinto the heart chambers. The therapeutic agent may include the patient'sown blood, which carries endogenous angiogenic agents. The surgeon maythen remove the helical coil by unscrewing it (through operation of theproximal end of the catheter), and perform the penetration on anothersite within the heart wall. The surgeon will be guided in selection ofsubsequent sites by the appearance of the contrast agent in thefluoroscopic image of the heart which clearly illustrates areaspreviously treated. Typically, the process is repeated to create 4 to 30wounds in the myocardium.

FIG. 19 shows the distal end of another fixation infusion catheter. Thehelix 1902 is larger than lumen 1904 in catheter body 1906 and cannot bepassed from end to end. However, helix 1902 can be retracted and parkedin enlarged distal portion 1916 of lumen 1904 to prevent its beingcaught on tissue during insertion and manipulation prior to engagementwith the heart. Parallel lumen 1912 in the wall of catheter body 1906provides both a means of infusing contrast adjacent to distally locatedhelix to improve visualization of structures adjacent to the helix aswell as the fixation of the helix, and a means of advancing the cathetersystem over a guide wire. Drug delivery lumen 1910 passes throughtorqueable pushable catheter body 1908 and connects up to distallylocated drug infusion helix 1902.

FIG. 20 shows a distal end of an infusion catheter system with pincherfixation element. Here, catheter body 2002 houses pincer fixation lumen2003, straight needle drug delivery lumen 2012, and utility lumen 2010which may be used for passing the system over a guidewire (the lumensare visible in the cross section of FIG. 20a), or for infusing contrastnear the distal end of the catheter system. The pincer fixation jaws2006 are opened by pushing on the stylet 2008 and applying tension onthe coil element 2004. As the coil 2004 is sized such that it stretchesslightly with this force, the jaws will exit the tubing 2002 as theyopen. Releasing the force on stylet mechanism 2008 allows the jaws toclose under a spring action not shown. Once secured to tissue such asthe endomyocardium in a fashion similar to a cardiac biopsy, contrastcan be infused down utility lumen 2010, to confirm the fixation of thejaws to the endocardium, and a needle can be advanced out of needlelumen 2012. Tubing 2002 may be formed of braiding reinforced Pebax orthe equivalent, and the durometer of the tubing resin would be reducedfrom proximal end to the distal end to optimize the pushability, andtorqueability with the flexibility in the heart chamber. For example ina 54 inch length (137 cm) of catheter body tubing, six sections fromproximal to distal could be specified: 25 inch (63.5 cm) length of NylonVestamid, 1 inch (2.54 cm) section of Pebax 72D, 20 inch (50.8 cm)section of Pebax 63D, 1 inch (2.5 cm) section of Pebax 55D, 1 inch (2.5cm) section of Pebax 40D, and a 25 inch (63.5 cm) section of Pebax 35D.The entire length would be reinforced with 0.0025″, 45 pics Per Inch (20pics per centimeter) stainless steel braiding.

Similar fixation mechanisms can be envisioned that involve dualintersecting precurved needles, dual needles that are hinged to becometrapped in trabeculae, polymer tine structures, and the like.

FIG. 21 shows a distal end of a fixation catheter. Here, the flexibilityof the distal end is optimized by incorporating a helical spring withthe distal helical infusion element. Approximately six French diameterbraided Pebax distal end of infusion catheter body 2102 houses a braidedpolyamide drive shaft 2104 with an interior diameter of 0.025 inches(0.63 mm) and an outer diameter of 0.045 inches (1.14 mm). Polyamidedrive shaft 2104 is connected to helical coil 2106 with an interiordiameter of 0.030 inches (0.76 mm) and an outer diameter of 0.039 inch(0.99 mm), the coil being a four filar right hand wound structure with0.004 inch (0.10 mm) diameter wire. Coil 2106 and polyamide drive shaft2104 are connected over a Pebax support with an interior diameter of0.024 inches (0.61 mm) and an outer diameter of 0.030 inches (0.76 mm).A very thin wall 35D Pebax tubing 2105 is melted over the junction ofthe drive shaft 2104 and the helical coil 2106 and pressure is appliedusing a appropriately sized heat shrink tubing which is subsequentlyremoved. Drug delivery tubing 2110, shown here to be single lumen tubinghaving an interior diameter of 0.010 inches (0.25 mm)and an outerdiameter of 0.016 inches (0.41 mm) passes within Pebax tubing 2108 andconnects to the stainless steel fixation and infusion helix formed ofhypodermic tubing having an interior diameter of 0.008 inches (0.20 mm)and an outer diameter of 0.016 inches (0.41 mm) and wound into a helixgeometry that has an interior diameter of 0.030 inches (0.97 mm) and anouter diameter of 0.058 inches (1.47 mm). Between the helical coil 2106and the drug delivery tubing 2110 is a Pebax tube with an interiordiameter of 0.016 inches (0.41 mm) and an outer diameter of 0.030 inch(0.76 mm) which adds mechanical support. The use of adhesives, epoxies,and molten polymer resin to adhere these structures together is achievedusing standard techniques. In one embodiment, the straight most proximalregion of the fixation helix is actually given a slight undulating bendsuch that it can be embedded in a Pebax material with a mechanical lockto prevent its detachment. This structure altogether provides a means tofix a structure to the heart through a guide catheter and providesubstantial flexibility to the distal end.

FIG. 22A through FIG. 22C show different preformed guide catheter shapesfor accessing different regions of the myocardium. They can be formed inthese shapes by placing them over a preformed steel mandrel and placingthem in an oven to allow the thermoplastic to reflow. Guide cathetersare typically used for accessing the coronary arteries, and these shapesare novel in that they have been designed to access different regions ofthe left ventricle from a retrograde trans-aortic technique. Guidecatheters are typically made of co-extruded or pull-truded stainlesssteel braiding and PTFE inner layer with an outer liner selected frompolyester, blended nylon, Pebax, and the like as has already beendescribed in the description of FIG. 21.

FIG. 22A shows a catheter 2201 with a 90 degree bend 2202 located twocentimeters from the distal end 2203 of the guide catheter with the bendradius being around 2 centimeters for accessing the postero-lateralventricular wall and adjacent regions. FIG. 22D shows a catheter 2211with a bend 2212 located 1 cm from distal end 2203 of the catheter anddeflected off axis (i.e., the long axis of the catheter body when atrest in a straight line) by about 30 degrees for accessing regionsadjacent to the inferior left ventricular apex. FIG. 22C shows acatheter 2231 with four bends 2232 each with a radius of curvature of1.5 cm. They are located 2 cm, 4 cm, 6 cm and 8 cm from distal end ofthe guide catheter and are all 90 degree bends but in oppositedirections as shown. The bend geometry is defined in relation to thelong axis of the guide catheter, labeled as item 2210. The distal end ofthe guide catheter thus is formed with a first 90 degree bend away fromthe long axis of the catheter at a point about 8 cm from the distal tip,creating a segment of guide catheter running perpendicular to the longaxis of the guide catheter, a second 90 degree bend toward the long axisof the guide catheter (bend located 6 cm from the distal tip of thecatheter), creating a segment of guide catheter running parallel to thelong axis of the catheter, a third 90 degree bend toward the long axisof the guide catheter (bend located 4 cm from the distal tip of theguide catheter), creating a second segment running perpendicular to thelong axis of the guide catheter, and a fourth 90 degree bend distally inline with the long axis of the guide catheter (bend located about 2 cmfrom the distal end of the guide catheter), creating a fourth segmentrunning parallel and co-linearly with the long axis of the catheter,with all bend segments and the proximal segment of the guide catheterlying in the same plane. This catheter is useful for delivering agentsadjacent to the anterior wall of the left ventricle as well as theanterior apical regions.

FIG. 23 shows a handle for a steerable infusion catheter system. Thehandle is comprised of two matching halves, the lower half 2318 and anupper half that is removed to illustrate the internal components of thehandle. One or more steering knobs connect to wheel 2308, which isprovided to pull on one or more pull wires in order to effect deflectionof the distal end of a steerable catheter. Set screw knob 2304 isattached to wheel 2308 with a screw extension that penetrates thehandpiece, so that the position of the wheel (and thus the deflection ofthe catheter) may be locked into place with set screw knob 2304 whichtightens upon the hand-piece 2318. The wheel 2308 is preferablyconstructed to allow passage of the infusion catheter either through orpast the wheel without interference. The wheel may be disposed againstthe wall of the hand-piece, leaving sufficient space in the center ofthe hand piece for passage of the infusion catheter, or it may havelongitudinal passageway 2350, as shown, which permits passage of theinfusion catheter through the wheel (although it may cause slight bendin the portion of the infusion catheter housed within the wheel), inwhich case the wheel must have a diameter sufficient to cause thedesired deflection of the guide catheter with wheel rotation limited bythe deflection of the infusion catheter within the wheel passageway. Theinfusion catheter is slidably disposed in the guide catheter and wheelbypass region, and fixable to the advancement slide 2310. Advancementslide 2310 is slidable within the hand-piece channel, and operable by athumb slide on the outside of the hand-piece connected to the slidethrough a slot in the outer surface of the hand-piece. The advancementslide is fixable (though not always fixed) to the infusion catheter sothat movement of the slide causes longitudinal movement of the infusioncatheter. The travel of the slide is sufficient to allow the distal endof the catheter, including the helical needle, to advance to a desiredextent, and may be limited to prevent the possibility that thepenetrating element can be extended completely through the myocardium.Once the position of the deflection is fixed by the operator, theinfusion catheter is advanced by advancing advancement slide 2310 inchannel hand piece channel. (This slide has a spring element 2312between its two halves to enable the infusion catheter body to passbetween fixation clamps in the hand-piece body which is provided inhalves (lower half 2318 is shown, and the upper half is not shown inorder to illustrate the internal parts of the hand-piece). The twohalves of the hand-piece are held together by screws 2306 and 2314.Slide 2310 slides axially within the handle advancing the catheterthrough a hollow wheel bypass region. Thumb screw 2316 is rotationallyfixed to the infusion catheter, so that rotation of the thumb screwcauses rotation of the infusion catheter and the helical needle at thedistal end of the infusion catheter. The infusion catheter proximal endwhich lies within the thumb screw region of the hand-piece islongitudinal slidable within the thumbscrews (to permit the slidingcontrolled by the side 2310), but rotationally fixed to the thumb screw2316. This may be accomplished by providing the proximal end of theinfusion catheter with longitudinally oriented ribs, and providing theinternal bore of the thumbscrew 2316 with teeth or cogs which engage theribs. Once advanced out of the distal end of the catheter, thepenetrating helical needle of the infusion catheter is quickly advancedinto the heart wall by rotation of thumb drum 2316 which is locked tothe catheter body when rotated. Space in the most proximal end of thecatheter hand piece is set aside for placement of the coiled tubing andluers that connect to the drug infusion catheter and the outer steerableguide body (not shown). Strain release 2302 prevents damage to the outerguide body. Within the outer catheter body there is also an O-ring sealwhich is proximal to an outer side port for accessing the outer catheterbody lumen. This O-ring is sized to prevent leakage of fluids from thespace between the outer guide catheter and the infusing catheter. Thelocation of the O-ring is distal to the longitudinal passageway andproximal to the distal end of the strain relief. Thus, a simplehandpiece that provides steerability for the outer catheter body,extension of an inner catheter body with a distal helical infusionelement, and rotation of said infusion element is provided.

In use, a surgeon or operator such as an interventional cardiologistinserts the catheter into the body at the femoral artery, using acut-down or the Seldinger technique to gain access to the artery. Theoperator then inserts a guidewire into the vasculature and advances aguidewire across the aortic valve into the heart. The operator theinserts the steerable guide catheter system over the guidewire, slidesit over the guidewire until the distal tip of the steerable guidecatheter is in the heart, and then removes the guidewire. After theguide wire is removed, the infusion catheter system is advanced throughthe steerable guide catheter, and the patient's own blood is infusedthrough the drug delivery lumen of the infusion catheter system so thatalbumin will bind to the polymer surface of the catheter lumen (therebypreventing the drugs to be delivered through the lumen from binding tothe lumen). Following infusion of blood down the drug delivery lumen, anappropriate medium such as saline or ringers solution is promptlydelivered. (Alternatively, saline or ringers containing albumin could bedelivered. Likewise, for agents where binding to the polymer walls ofthe catheter is not an issue, this step would be skipped.) After thelumen of the infusion catheter has been so prepared, the helicalinfusion needle is screwed into appropriate regions of the heart wall.Contrast is infused through the annular lumen or space between the guidecatheter and the infusion catheter to confirm the position of the systemunder fluoroscopy, and the system is used to inject therapeutic agents,such as microspheres larger than 15 um in diameter, to a depth withinthe myocardium. The operator forces the plunger of syringe 1206 (FIG.12) of the therapeutic agent reservoir to force the therapeutic agentsinto the heart. The amount displaced from the syringe should be equal tothe desired dose minus the dead space downstream of valve 1210.Following operation of the therapeutic reservoir syringe, the operatorforces passive agent by operation of the plunger of syringe 1204,forcing an amount of passive agent into the drug delivery lumen that isequal to the dead space, to ensure that the entire dead space is clearedof the desired dose of therapeutic agent and that the desired dose isactually delivered to the heart tissue. The catheter is maintainedengaged with the heart for a period of time sufficient to ensure thatthe injected therapeutic agent is absorbed by the heart tissue and doesnot merely leak out of wound caused by the penetrating helical needle.The catheter is then carefully disengaged from the heart tissue byunscrewing the helix through rotation of the appropriate portion of theproximal handling mechanism. If appropriate, the procedure may berepeated at different locations within the heart.

Fixation infusion systems provide time to confirm the position of thehelical needle or other fixation device within the heart during aninterventional procedure using electrical signals within the hearttissue, standard fluoroscopic imaging techniques, fluoroscopictechniques in which contrast is infused adjacent to the penetratingelement and/or at a depth within the tissue, ultrasound imagingtechniques, or even electromagnetic imaging techniques such as thosedeveloped by Johnson and Johnson BioSense. Where fluoroscopy is used,contrast agent may be injected through the steerable guide catheter 1624(FIGS. 16 and 17, or through the annular lumen 1252 of the infusioncatheter system. Additionally, contrast agent may be injected into theheart wall through the helical needle after it has been driven into themyocardium, so that the depth of helical needle within the heart wallcan be confirmed.

Fixating infusion systems for delivery of therapeutic agents optimizesthe control over dosing. Certainty as to the position of the injectingneedle eliminates the potential for delivering agents inappropriately,and assures the operator that agents have been delivered to a depthwithin the tissue. The fixation approach provides the ability to flushthe deadspace of the catheter after a procedure to eliminate thispotential dosing error, and allows for control over redistribution ofthe infused agent by controlling the volume and time course of the agentinfused. In the case of the helical fixation means, the long path lengthof the penetrating element (i.e., the needle track) adds the addedadvantage that agents delivered to a depth within the myocardium willnot leak back into the heart chambers, and more dose will reach thetarget tissue. This has huge advantages in intra-myocardial delivery ofmicrosphere controlled release systems which have been sized so thatthey will not migrate within the myocardium, but which are large enoughto cause adverse embolic events should they escape into the leftventricle, but is advantageous also for conservation of all injectedtherapeutic agents. Typically, when therapeutic agents are injected intothe heart wall with a straight needle, much of the therapeutic agentleaks backward, out of the penetration wound (the needle track), andinto the endocardial pace (and subsequently into the vascular system toimpose systemic pharmacological and thrombotic/embolic effects on thepatient). When injecting therapeutic agents with a helical needle, andmaintaining the helical needle in place during injection, the rate ofback-leakage is diminished. Thus, for a given desired resident dose (thedose remaining in the myocardium after back-leakage of the leakingvolume of the therapeutic agent), the necessary injected dose need onlybe about 2 to 10 times the desired resident dose. Where the therapeuticagent is comprised of macromolecules 10 kilo Daltons and above, and 0.5cc of therapeutic agent was slowly injected over 30 seconds, followed byinjection of 0.2 cc of passive agent injected over 30 seconds, followedby continued retention of the helical needle in the needle track forabout 30 seconds, 25% of the dose was retained in the myocardium 1.5hours after injection. In this case, injection of a dose no larger thanabout 3-4 times the volume of the desired resident dose is sufficient toprovide the desired resident dose.

The fixation means improves physician control of delivering therapeuticagents, genes, and cells for molecular and cellular therapeuticcardiology. The physician can confirm that delivery is appropriate, caninfuse agents over any specified time course to a depth within thetarget tissue, and the physician can deliver other agents at the samesites without fear that the catheter system has moved.

These same systems are useful for a new type of diagnostic procedure inwhich a fluid agent is infused to a depth within a particular tissue andthe fluid is then withdrawn through the same infusion element. In thisway a type of fluid biopsy may be performed and the mileau within thetissue may be assessed for the presence of markers of different diseasestates.

Further the devices described wherein the guide catheter is designed tohave a space between it and the fixation systems may be used as a leftventricular angiography catheter with controlled fixation for improvedvisualization of specific regions of interest within the heart. In use,the endocardial space is accessed as described above, through thevascular system, and the helical needle is driven into the heart wallnear the site which is to be visualized in angiography. After thecatheter is anchored to the heart wall, angiographic contrast agent isdelivered through the guide catheter or through the infusion catheterbody (1214 and 1750, for example). The contrast fluid may be injected athigh pressure without whipping within the heart and wandering away fromthe target to be imaged.

Catheters with a straight cylindrical lumen from one end to the othercould be used with a thin bundle of optical fibers passed through thelumen to create channels within the heart for improving the flow ofpharmacological agents within the heart. In other variations, the thinoptical fiber could be replaced with a thin RF electrode structure whichcould literally burn channels within the tissue. Such procedures couldbe viewed as a combined transmyocardial revascularization (TMR) and drugdelivery. For example, after a catheter is implanted and agents aredelivered to minimize re-flow damage to the heart, simple TMR could beintroduced with a centrally placed optical fiber. Subsequent to the TMR,angiogenic growth factors could be introduced

Thus, while the preferred embodiments of the devices and methods havebeen described in reference to the environment in which they weredeveloped, they are merely illustrative of the principles of theinventions. Other embodiments and configurations may be devised withoutdeparting from the spirit of the inventions and the scope of theappended claims.

We claim:
 1. The method of delivery of a therapeutic agent selected fromthe set of macromolecule, gene therapy preparation, microspheres, ormicelles to a depth within the myocardium including the steps of:providing a catheter adapted for insertion into the heart, said catheterhaving a proximal end and a distal end, said catheter having a fixatingpenetrating element secured to the distal end thereof, said catheterhaving a drug delivery lumen extending from the proximal end to thedistal end of the catheter and a drug delivery port at the distal end ofthe catheter communicating from the drug delivery lumen to the exteriorof the catheter; inserting the catheter into the heart, and manipulatingthe fixating penetrating element to engage the heart wall and releasablyconnect the catheter distal tip to the heart wall; manipulating thefixating penetrating element to cause it to penetrate the heart wall;and infusing the therapeutic agent to a depth within the heart wall. 2.The method of claim 1 further comprising the steps of: providing thefixating penetrating element comprising a helical structure; andmanipulating the fixating penetrating element to engage the heart wallby screwing the helical structure into the heart wall.
 3. The method ofclaim 1 further comprising the steps of: providing the fixatingpenetrating element comprising a plurality of intersecting penetratingelements; and manipulating the intersecting penetrating elements toengage the heart wall by forcing the intersecting penetrating elementsinto the heart wall.
 4. The method of claim 1 further comprising thesteps of: providing the fixating penetrating element comprising aplurality of jaws operable from the proximal end of the catheter to openand close and a penetrating needle longitudinally movable from thecatheter into the heart wall; and manipulating the jaws to engage theheart wall and pushing the penetrating needle into the heart wall. 5.The method of claim 1, 2, 3 or 4 in which a confirmatory step occursafter the catheter is attached and before the agent is infused into thetissue, in which contrast agent is infused into the heart chamber tovisually confirm that the catheter is positioned appropriately.
 6. Themethod of claim 1, 2, 3 or 4 in which a confirmatory step occurs afterthe catheter is attached and before the agent is infused into thetissue, in which contrast agent is infused into the heart tissue tovisually confirm that the catheter is positioned appropriately.
 7. Themethod of claim 1, 2, 3 or 4 further comprising the step of: confirmingthe position of the catheter distal end within the heart by infusingcontrast agent into the heart chamber through the catheter.
 8. Themethod of claim 5 in which the contrast is delivered through an outerguide catheter system.
 9. The method of claim 7 further comprising thesteps of: providing a guide catheter adapted for percutaneous insertioninto the heart, said guide catheter having a proximal end and a distalend and a lumen extending from the proximal end to the distal end;inserting the guide catheter into the heart; inserting the catheterthrough the guide catheter lumen and into the heart; delivering contrastagent through the guide catheter lumen to the heart.
 10. The method ofclaim 1 in which the contrast is delivered through a distal port in thedrug delivery catheter which is fixed to the heart wall.
 11. The methodof claim 1 further comprising the steps of: infusing a passive agent ina volume equivalent to 1 to 5 times the volume of the drug deliverylumen.
 12. The method of claim 1 in which the volume of the drugdelivery lumen in the delivery catheter is between 0.05 and 0.25milliliters.
 13. A catheter for interstitial delivery that has twolumens which connect to one another prior to the distal penetratingelement.
 14. A drug delivery catheter for injection of small doses of atherapeutic agent into the heart wall, said drug delivery cathetercomprising: a catheter tube adapted for percutaneous insertion into theheart, said catheter having a distal end adapted for insertion in to theheart and a proximal end housed within a housing; a first lumenextending through the catheter, said lumen having a distal end adaptedfor fluid injection into the heart and a proximal end adapted forconnection to one or more fluid reservoirs; a first fluid reservoirreleasably secured to the housing; a second fluid reservoir releasablysecured to the housing; a valve communicating with the proximal end ofthe first lumen, said valve permitting selective connection of the fluidsources to the proximal end of the first lumen; a first fluid connectionconnecting the first fluid reservoir to the valve; a second fluidconnection connecting the second fluid reservoir to the valve; a firstactuator for forcing fluid from the first fluid reservoir through thevalve and into the first lumen; a second actuator operably connected tothe second fluid reservoir for forcing fluid from the second fluidreservoir through the valve and into the first lumen; and a penetratingneedle disposed on the distal tip of the first lumen, said penetratingneedle adapted to penetrate the heart wall.
 15. The device of claim 14wherein the first fluid connection comprises a length of distensibletubing.
 16. The device of claim 14 further comprising: a second lumenextending from the housing to the distal end of the catheter, and athird fluid connection in fluid communication with the proximal end ofsecond lumen and adapted for connection to a fluid source, and a fluidport in the catheter at the distal end of the catheter providing a fluidpathway between the second lumen and the exterior of the catheter.
 17. Amethod of injecting therapeutic agents in to the body, said methodcomprising: providing a drug delivery catheter for injection small dosesof therapeutic agent into the body, said drug delivery cathetercomprising: a catheter tube adapted for percutaneous insertion into theheart, said catheter having a distal end adapted for insertion in to theheart and a proximal end housed within a housing; a first lumenextending through the catheter, said lumen having a distal end adaptedfor fluid injection into the heart and a proximal end adapted forconnection to one or more fluid reservoirs; a first fluid reservoirreleasably secured within the housing; a second fluid reservoirreleasably secured within the housing; a valve communicating with theproximal end of the first lumen, said valve permitting selectiveconnection of the fluid sources to the proximal end of the first lumen;a first fluid connection connecting the first fluid reservoir to thevalve; a second fluid connection connecting the second fluid reservoirto the valve; a first actuator for forcing fluid from the first fluidreservoir through the valve and into the first lumen; a second actuatoroperably connected to the second fluid reservoir for forcing fluid fromthe second fluid reservoir through the valve and into the first lumen;placing a first fluid in the first fluid reservoir; placing a secondfluid in the second fluid reservoir; forcing a predetermined volume ofthe first fluid from the first fluid reservoir into the first lumen; andforcing a volume of the second fluid from the second fluid reservoirinto the first lumen.
 18. The method of claim 17 wherein; the step offorcing a volume of second fluid from the second fluid reservoir intothe first lumen precedes the step of forcing a predetermined volume ofthe first fluid from the first fluid reservoir into the first lumen. 19.The method of claim 17 wherein; the step of forcing a volume of secondfluid from the second fluid reservoir into the first lumen is repeatedafter the step of forcing a predetermined volume of the first fluid fromthe first fluid reservoir into the first lumen.
 20. The method of claim17 further comprising: providing a therapeutic agent in the first fluid;providing a passive agent in the second fluid.
 21. The method of claim17 further comprising: providing a therapeutic agent in the first fluid;providing an activating agent in the second fluid, wherein saidactivating agent interacts with the first fluid to alter the firstfluid.
 22. The method of claim 17 further comprising: providing atherapeutic agent in the first fluid, wherein said therapeutic agentcomprises a therapeutic compound encapsulated in a liposome capsule;providing an activating agent in the second fluid, wherein saidactivating fluid has a pH which destabilizes the liposome capsules inthe first fluid.
 23. A drug delivery catheter for injection of smalldoses of a therapeutic agent into the heart wall, said drug deliverycatheter comprising: a catheter tube adapted for insertion into theheart, said catheter having a distal end adapted for insertion into theheart and a proximal end housed within a housing; a first lumenextending through the catheter, said lumen having a distal end adaptedfor fluid injection into the heart through a fixating penetratingelement, said fixating penetrating element having a base, and a proximalend connected to a first at least one fluid reservoir; and a secondlumen extending through the catheter, said second lumen having aproximal end connected to a second at least one fluid reservoir, andsaid lumen having a distal end terminating at the base of a fixatingpenetrating element.
 24. A catheter as in claim 23 where the fixatingpenetrating element is a hollow helix.